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Pei L, Liu Y, Liu L, Gao S, Gao X, Feng Y, Sun Z, Zhang Y, Wang C. Roles of cancer-associated fibroblasts (CAFs) in anti- PD-1/PD-L1 immunotherapy for solid cancers. Mol Cancer 2023; 22:29. [PMID: 36759842 PMCID: PMC9912573 DOI: 10.1186/s12943-023-01731-z] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 01/24/2023] [Indexed: 02/11/2023] Open
Abstract
In recent years, breakthroughs have been made in tumor immunotherapy. However, tumor immunotherapy, particularly anti-PD-1/PD-L1 immune checkpoint inhibitors, is effective in only a small percentage of patients in solid cancer. How to improve the efficiency of cancer immunotherapy is an urgent problem to be solved. As we all know, the state of the tumor microenvironment (TME) is an essential factor affecting the effectiveness of tumor immunotherapy, and the cancer-associated fibroblasts (CAFs) in TME have attracted much attention in recent years. As one of the main components of TME, CAFs interact with cancer cells and immune cells by secreting cytokines and vesicles, participating in ECM remodeling, and finally affecting the immune response process. With the in-depth study of CAFs heterogeneity, new strategies are provided for finding targets of combination immunotherapy and predicting immune efficacy. In this review, we focus on the role of CAFs in the solid cancer immune microenvironment, and then further elaborate on the potential mechanisms and pathways of CAFs influencing anti-PD-1/PD-L1 immunotherapy. In addition, we summarize the potential clinical application value of CAFs-related targets and markers in solid cancers.
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Affiliation(s)
- Liping Pei
- grid.412633.10000 0004 1799 0733Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China ,grid.412633.10000 0004 1799 0733Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yang Liu
- grid.414008.90000 0004 1799 4638Department of Radiotherapy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Lin Liu
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. .,Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Shuochen Gao
- grid.412633.10000 0004 1799 0733Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Xueyan Gao
- grid.412633.10000 0004 1799 0733Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yudi Feng
- grid.412633.10000 0004 1799 0733Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Zhenqiang Sun
- Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. .,Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Yan Zhang
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
| | - Chengzeng Wang
- Department of Ultrasound, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China. .,Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China.
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Biodetection Techniques for Quantification of Chemokines. CHEMOSENSORS 2022. [DOI: 10.3390/chemosensors10080294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Chemokines are a class of cytokine whose special properties, together with their involvement and relevant role in various diseases, make them a restricted group of biomarkers suitable for diagnosis and monitoring. Despite their importance, biodetection techniques dedicated to the selective determination of one or more chemokines are very scarce. For some years now, the critical diagnosis of inflammatory diseases by detecting both cytokine and chemokine biomarkers, has had a strong impact on the development of multiple detection platforms. However, it would be desirable to implement methodologies with a higher degree of selectivity for chemokines, in order to provide more precise information. In addition, better development of biosensor technology applied to this specific field would make it possible to address the main challenges of detection methods for several diseases with a high incidence in the population, avoiding high costs and low sensitivity. Taking this into account, this review aims to present the state of the art of chemokine biodetection techniques and emphasize the role of these systems in the prevention, monitoring and treatment of various diseases associated with chemokines as a starting point for future developments that are also analyzed throughout the article.
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Poulsen KL, Cajigas-Du Ross CK, Chaney JK, Nagy LE. Role of the chemokine system in liver fibrosis: a narrative review. DIGESTIVE MEDICINE RESEARCH 2022; 5:30. [PMID: 36339901 PMCID: PMC9632683 DOI: 10.21037/dmr-21-87] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND OBJECTIVE Liver fibrosis is a disease with characteristics of an aberrant wound healing response. Fibrosis is commonly the end-stage for chronic liver diseases like alcohol-associated liver disease (ALD), metabolic-associated liver disease, viral hepatitis, and hepatic autoimmune disease. Innate immunity contributes to the progression of many diseases through multiple mechanisms including production of pro-inflammatory mediators, leukocyte infiltration and tissue injury. Chemokines and their receptors orchestrate accumulation and activation of immune cells in tissues and are associated with multiple liver diseases; however, much less is known about their potential roles in liver fibrosis. This is a narrative review of current knowledge of the relationship of chemokine biology to liver fibrosis with insights into potential future therapeutic opportunities that can be explored in the future. METHODS A comprehensive literature review was performed searching PubMed for relevant English studies and texts regarding chemokine biology, chronic liver disease and liver fibrosis published between 1993 and 2021. The review was written and constructed to detail the intriguing chemokine biology, the relation of chemokines to tissue injury and resolution, and identify areas of discovery for fibrosis treatment. KEY CONTENT AND FINDINGS Chemokines are implicated in many chronic liver diseases, regardless of etiology. Most of these diseases will progress to fibrosis without appropriate treatment. The contributions of chemokines to liver disease and fibrosis are diverse and include canonical roles of modulating hepatic inflammation as well as directly contributing to fibrosis via activation of hepatic stellate cells (HSCs). Limited clinical evidence suggests that targeting chemokines in certain liver diseases might provide a therapeutic benefit to patients with hepatic fibrosis. CONCLUSIONS The chemokine system of ligands and receptors is a complex network of inflammatory signals in nearly all diseases. The specific sources of chemokines and cellular targets lend unique pathophysiological consequences to chronic liver diseases and established fibrosis. Although most chemokines are pro-inflammatory and contribute to tissue injury, others likely aid in the resolution of established fibrosis. To date, very few targeted therapies exist for the chemokine system and liver disease and/or fibrosis, and further study could identify viable treatment options to improve outcomes in patients with end-stage liver disease.
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Affiliation(s)
- Kyle L. Poulsen
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Christina K. Cajigas-Du Ross
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Jarod K. Chaney
- Department of Anesthesiology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Laura E. Nagy
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
- Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH, USA
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Changes in serum interferon-γ-inducible protein-10 levels and liver stiffness among chronic hepatitis C Egyptian patients in response to directly acting antiviral agents. Eur J Gastroenterol Hepatol 2021; 33:e335-e340. [PMID: 33470694 DOI: 10.1097/meg.0000000000002059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Interferon-γ inducible protein-10 (IP-10) is chemokine biomarker of liver inflammation, elevated in patients with chronic hepatitis C infection. AIMS Investigating if changes in serum IP-10 levels in response to directly acting antiviral agents (DAAs) treatment for chronic HCV patients are paralleled by changes in liver stiffness measurements (LSM), and assessing role of using serum IP-10 as a noninvasive accurate method to predict changes in hepatic necro-inflammation and fibrosis. MATERIAL AND METHODS A prospective observational study included 92 Egyptian chronic HCV patients, who received treatment with sofosbuvir with daclatasvir regimen. Patients were classified into two groups; group I (53 patients) with non to mild significant liver fibrosis (F0-F1), and group II (39 patients) with significant to advanced liver fibrosis (F2-F4). Fibroscan and serum IP-10 were assessed pretreatment and 3 months after end of treatment. RESULTS All patients achieved SVR. Both IP-10 and LSM showed significant decline after treatment in both groups. No significant correlation was found between changes in LSM and IP-10. IP-10 detected liver cirrhosis at cut off level of 17.8 pg/ml, with 75% sensitivity and 73.86% specificity, with area under the curve = 0.66, however, IP-10 had no statistical significance in detecting advanced fibrosis. CONCLUSION IP-10 might be of significance as a noninvasive predictor of liver cirrhosis. IP-10 significant decline post-DAAs treatment in chronic HCV genotype IV infected patients reflects significant improvement in fibrosis stage and hepatic necro-inflammation in response to treatment. No significant correlation was detected in the changes of both IP-10 and LSM.
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Shrivastava S, Kottilil S, Sherman KE, Masur H, Tang L. CCR5+ T-Cells Homed to the Liver Exhibit Inflammatory and Profibrogenic Signatures in Chronic HIV/HCV-Coinfected Patients. Viruses 2021; 13:v13102074. [PMID: 34696504 PMCID: PMC8539814 DOI: 10.3390/v13102074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/08/2021] [Accepted: 10/10/2021] [Indexed: 11/16/2022] Open
Abstract
Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to the inflamed liver and contribute to enhanced fibrogenesis. We compared the peripheral and intrahepatic CCR5 expression on CD4+ and CD8+ T cells in 21 HIV/HCV-coinfected patients with 14 chronic HCV monoinfected patients. Using 12-color flow cytometry, phenotypic and functional characterization of CCR5+ and negative cells pre- and post-stimulation with HCV genotype specific overlapping pooled peptides was conducted. Patients with HIV/HCV coinfection had significantly more CD4+CCR5+ and CD8+CCR5+ T cells in the liver as compared with peripheral blood (p = 0.0001 for both). Compared with patients with HCV monoinfection, patients with HIV/HCV coinfection also had fewer peripheral CD4+CCR5+ and CD8+CCR5+ T cells (p = 0.02, p = 0.001 respectively), but more intrahepatic CD4+CCR5+ and CD8+CCR5+ cells (p = 0.0001 for both). Phenotypic analysis of CCR5+ sorted cells demonstrated an increased expression of markers of exhaustion, senescence, immune activation and liver homing (PD1, CD57, CD38, HLADR, and CXCR3). Post-stimulation with HCV peptides, CCR5+ T cells secreted more proinflammatory and profibrogenic cytokines and chemokines rather than antiviral cytokines. Phenotypic and functional analyses of CCR5+ T cells in HIV/HCV-coinfected patients revealed a pathogenic role for CCR5+ T cells in hepatic fibrogenesis. These cells are functionally proinflammatory, pro-fibrogenic and preferentially accumulate in liver, accelerating fibrosis. These findings suggest that targeting CCR5 may be a therapeutic strategy for be ameliorating liver fibrosis.
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Affiliation(s)
- Shikha Shrivastava
- Laboratory of Adjuvant and Antigen Research, US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA;
| | - Shyam Kottilil
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Program in Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA
| | - Kenneth E. Sherman
- Division of Digestive Diseases, University of Cincinnati, Cincinatti, OH 45267, USA;
| | - Henry Masur
- National Institutes of Health, Bethesda, MD 20892, USA;
| | - Lydia Tang
- Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
- Program in Oncology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD 21201, USA
- Correspondence:
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Zhou JY, Song LW, Yuan R, Lu XP, Wang GQ. Prediction of hepatic inflammation in chronic hepatitis B patients with a random forest-backward feature elimination algorithm. World J Gastroenterol 2021; 27:2910-2920. [PMID: 34135561 PMCID: PMC8173380 DOI: 10.3748/wjg.v27.i21.2910] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 04/01/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Persistent liver inflammatory damage is the main risk factor for developing liver fibrosis, cirrhosis, and even hepatocellular carcinoma in chronic hepatitis B (CHB) patients. Thus, accurate prediction of the degree of liver inflammation is a high priority and a growing medical need.
AIM To build an effective and robust non-invasive model for predicting hepatitis B-related hepatic inflammation.
METHODS A total of 650 treatment-naïve CHB (402 HBeAg-positive and 248 HBeAg-negative) patients who underwent liver biopsy were enrolled in this study. Histological inflammation grading was assessed by the Ishak scoring system. Serum quantitative hepatitis B core antibody (qAnti-HBc) levels and 21 immune-related inflammatory factors were measured quantitatively using a chemiluminescent microparticle immunoassay. A backward feature elimination (BFE) algorithm utilizing random forest (RF) was used to select optional features and construct a combined model. The diagnostic abilities of the model or variables were evaluated based on the estimated area under the receiver operating characteristics curve (AUROC) and compared using the DeLong test.
RESULTS Four features were selected to predict moderate-to-severe inflammation in CHB patients using the RF-BFE method. These predictive features included qAnti-HBc, ALT, AST, and CXCL11. Spearman’s correlation analysis indicated that serum qAnti-HBc, ALT, AST, and CXCL11 levels were positively correlated with the histology activity index (HAI) score. These selected features were incorporated into the model to establish a novel model named I-3A index. The AUROC [0.822; 95% confidence interval (CI): 0.790-0.851] of the I-3A index was significantly increased compared with qAnti-HBc alone (0.760, 95%CI: 0.724-0.792, P < 0.0001) in all CHB patients. The use of an I-3A index cutoff value of 0.41 produced a sensitivity of 69.17%, specificity of 81.44%, and accuracy of 73.8%. Additionally, the I-3A index showed significantly improved diagnostic performance for predicting moderate-to-severe inflammation in HBeAg-positive and HBeAg-negative CHB patients (0.829, 95%CI: 0.789-0.865 and 0.810, 95%CI: 0.755-0.857, respectively).
CONCLUSION The selected features of the I-3A index constructed using the RF-BFE algorithm can effectively predict moderate-to-severe liver inflammation in CHB patients.
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Affiliation(s)
- Ji-Yuan Zhou
- Department of Gastroenterology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, Guangdong Province, China
| | - Liu-Wei Song
- School of Public Health, Xiamen University, Xiamen 361005, Fujian Province, China
| | - Rong Yuan
- Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Xiao-Ping Lu
- Intervention and Cell Therapy Center, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Gui-Qiang Wang
- Department of Infectious Disease, Peking University First Hospital, Beijing 100034, China
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Huynh C, Henrich A, Strasser DS, Boof ML, Al-Ibrahim M, Meyer Zu Schwabedissen HE, Dingemanse J, Ufer M. A Multipurpose First-in-Human Study With the Novel CXCR7 Antagonist ACT-1004-1239 Using CXCL12 Plasma Concentrations as Target Engagement Biomarker. Clin Pharmacol Ther 2021; 109:1648-1659. [PMID: 33406277 DOI: 10.1002/cpt.2154] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/04/2020] [Indexed: 11/09/2022]
Abstract
The C-X-C chemokine receptor 7 (CXCR7) has evolved as a promising, druggable target mainly in the immunology and oncology fields modulating plasma concentrations of its ligands CXCL11 and CXCL12 through receptor-mediated internalization. This "scavenging" activity creates concentration gradients of these ligands between blood vessels and tissues that drive directional cell migration. This randomized, double-blind, placebo-controlled first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-1004-1239, a first-in-class drug candidate small-molecule CXCR7 antagonist. Food effect and absolute bioavailability assessments were also integrated in this multipurpose study. Healthy male subjects received single ascending oral doses of ACT-1004-1239 (n = 36) or placebo (n = 12). At each of six dose levels (1-200 mg), repeated blood sampling was done over 144 hours for pharmacokinetic/pharmacodynamic assessments using CXCL11 and CXCL12 as biomarkers of target engagement. ACT-1004-1239 was safe and well tolerated up to the highest tested dose of 200 mg. CXCL12 plasma concentrations dose-dependently increased and more than doubled compared with baseline, indicating target engagement, whereas CXCL11 concentrations remained unchanged. An indirect-response pharmacokinetic/pharmacodynamic model well described the relationship between ACT-1004-1239 and CXCL12 concentrations across the full dose range, supporting once-daily dosing for future clinical studies. At doses ≥ 10 mg, time to reach maximum plasma concentration ranged from 1.3 to 3.0 hours and terminal elimination half-life from 17.8 to 23.6 hours. The exposure increase across the dose range was essentially dose-proportional and no relevant food effect on pharmacokinetics was determined. The absolute bioavailability was 53.0% based on radioactivity data after oral vs. intravenous 14 C-radiolabeled microtracer administration of ACT-1004-1239. Overall, these comprehensive data support further clinical development of ACT-1004-1239.
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Affiliation(s)
- Christine Huynh
- Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland.,University of Basel, Basel, Switzerland
| | | | | | | | | | | | | | - Mike Ufer
- Idorsia Pharmaceuticals Ltd, Allschwil, Switzerland
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Shigeta K, Matsui A, Kikuchi H, Klein S, Mamessier E, Chen IX, Aoki S, Kitahara S, Inoue K, Shigeta A, Hato T, Ramjiawan RR, Staiculescu D, Zopf D, Fiebig L, Hobbs GS, Quaas A, Dima S, Popescu I, Huang P, Munn LL, Cobbold M, Goyal L, Zhu AX, Jain RK, Duda DG. Regorafenib combined with PD1 blockade increases CD8 T-cell infiltration by inducing CXCL10 expression in hepatocellular carcinoma. J Immunother Cancer 2020; 8:jitc-2020-001435. [PMID: 33234602 PMCID: PMC7689089 DOI: 10.1136/jitc-2020-001435] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND AND PURPOSE Combining inhibitors of vascular endothelial growth factor and the programmed cell death protein 1 (PD1) pathway has shown efficacy in multiple cancers, but the disease-specific and agent-specific mechanisms of benefit remain unclear. We examined the efficacy and defined the mechanisms of benefit when combining regorafenib (a multikinase antivascular endothelial growth factor receptor inhibitor) with PD1 blockade in murine hepatocellular carcinoma (HCC) models. BASIC PROCEDURES We used orthotopic models of HCC in mice with liver damage to test the effects of regorafenib-dosed orally at 5, 10 or 20 mg/kg daily-combined with anti-PD1 antibodies (10 mg/kg intraperitoneally thrice weekly). We evaluated the effects of therapy on tumor vasculature and immune microenvironment using immunofluorescence, flow cytometry, RNA-sequencing, ELISA and pharmacokinetic/pharmacodynamic studies in mice and in tissue and blood samples from patients with cancer. MAIN FINDINGS Regorafenib/anti-PD1 combination therapy increased survival compared with regofarenib or anti-PD1 alone in a regorafenib dose-dependent manner. Combination therapy increased regorafenib uptake into the tumor tissues by normalizing the HCC vasculature and increasing CD8 T-cell infiltration and activation at an intermediate regorafenib dose. The efficacy of regorafenib/anti-PD1 therapy was compromised in mice lacking functional T cells (Rag1-deficient mice). Regorafenib treatment increased the transcription and protein expression of CXCL10-a ligand for CXCR3 expressed on tumor-infiltrating lymphocytes-in murine HCC and in blood of patients with HCC. Using Cxcr3-deficient mice, we demonstrate that CXCR3 mediated the increased intratumoral CD8 T-cell infiltration and the added survival benefit when regorafenib was combined with anti-PD1 therapy. PRINCIPAL CONCLUSIONS Judicious regorafenib/anti-PD1 combination therapy can inhibit tumor growth and increase survival by normalizing tumor vasculature and increasing intratumoral CXCR3+CD8 T-cell infiltration through elevated CXCL10 expression in HCC cells.
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Affiliation(s)
- Kohei Shigeta
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Aya Matsui
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Hiroto Kikuchi
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Sebastian Klein
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA.,Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Emilie Mamessier
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ivy X Chen
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shuichi Aoki
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shuji Kitahara
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Koetsu Inoue
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Ayako Shigeta
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Tai Hato
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rakesh R Ramjiawan
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Daniel Staiculescu
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Dieter Zopf
- Drug Discovery, Bayer Pharma AG, Berlin, Germany
| | - Lukas Fiebig
- Drug Discovery, Bayer Pharma AG, Berlin, Germany
| | - Gabriela S Hobbs
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Alexander Quaas
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | - Simona Dima
- Center for General Surgery and Liver Transplantation, Clinical Institute Fundeni, Bucharest, Romania
| | - Irinel Popescu
- Center for General Surgery and Liver Transplantation, Clinical Institute Fundeni, Bucharest, Romania
| | - Peigen Huang
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lance L Munn
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Mark Cobbold
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lipika Goyal
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Andrew X Zhu
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Rakesh K Jain
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Dan G Duda
- Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Fu WK, Cao J, Mi NN, Huang CF, Gao L, Zhang JD, Yue P, Bai B, Lin YY, Meng WB. Cytokines predict virological response in chronic hepatitis B patients receiving peginterferon alfa-2a therapy. World J Clin Cases 2020; 8:2255-2265. [PMID: 32548156 PMCID: PMC7281045 DOI: 10.12998/wjcc.v8.i11.2255] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 04/18/2020] [Accepted: 04/27/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus infection remains a major global public health problem. Peginterferon-alpha-2a (PEG-IFN) has direct antiviral and immunoregulatory effects, and it has become one of the first choice drugs for the treatment of chronic hepatitis B (CHB). Cytokines play an important role in immunity, and they directly inhibit viral replication and indirectly determine the predominant pattern of the host immune response.
AIM To determine the correlation between cytokine/chemokine expression levels and response to PEG-IFN treatment in patients with CHB.
METHODS Forty-six kinds of cytokines were analyzed before PEG-IFN therapy and at 24 wk during therapy in 26 CHB patients.
RESULTS The monokine induced by INF-γ (CXCL9) and serum interferon-inducible protein 10 ( IP-10) levels at baseline were higher in virological responders than in non-virological responders (NRs) and decreased during treatment, whereas the NRs did not exhibit significant changes. The macrophage inflammatory protein 1d (MIP-1d) levels at baseline and during treatment were significantly higher in the virological responders than in the NRs, while thymus and activation-regulated chemokine (TARC) levels at baseline and during treatment were significantly lower in the virological responders than in the NRs. The CXCL9, IP-10, MIP-1d, and TARC baseline levels exhibited the expected effects for interferon treatment. The area under the receiver operating characteristic curve values of CXCL9, IP-10, MIP-1d, and TARC for predicting virological responses were 0.787, 0.799, 0.787, and 0.77 (P = 0.01, 0.013, 0.01, and 0.021), respectively.
CONCLUSION We found that cytokine levels before and during treatment may represent potential biomarkers to select CHB patients who can respond to PEG-IFN. Therefore, cytokines can be used as an indicator of antiviral drug selection before CHB treatment.
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Affiliation(s)
- Wen-Kang Fu
- The First Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jie Cao
- The First Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Laboratory Department of the First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ning-Ning Mi
- The First Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Chong-Fei Huang
- The First Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Long Gao
- The First Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Jin-Duo Zhang
- Special Minimally Invasive Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Ping Yue
- Special Minimally Invasive Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Bing Bai
- Special Minimally Invasive Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yan-Yan Lin
- Special Minimally Invasive Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Wen-Bo Meng
- The First Clinical Medical School, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Special Minimally Invasive Surgery Department, The First Hospital of Lanzhou University, Lanzhou 730000, Gansu Province, China
- Institute of Genetics, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
- Institute of Hepatopancreatobiliary of Gansu Province, Lanzhou 730000, Gansu Province, Chinao
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou 730000, Gansu Province, China
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10
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Afzal M, Ali A, Sheikh N, Rafique S, Idrees M. Peripheral Expression of CXCL10 Gene in Chronic Hepatitis C Patients Treated with Sofosbuvir, Daclatasvir, and Ribavirin. J Interferon Cytokine Res 2020; 40:301-309. [PMID: 32486887 DOI: 10.1089/jir.2019.0185] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatitis C virus (HCV) causes persistent infection and invades host's innate and adaptive immune systems. During the eradication of this pathogen, the components of immune system may cause bystander damage to host, which might be even worse than the viral pathogenesis. Thus, the therapy should not only eliminate primary virus infection but also improve the inflammatory immune responses. The breakthrough of interferon free direct acting antiviral (DAA) drugs has provided the opportunity to unravel the association of HCV with immune response. This study aimed to examine the expression level of C-X-C motif chemokine ligand 10 (CXCL10) in the Peripheral blood mononuclear cells (PBMCs) of HCV infected patients treated with DAAs + Ribavirin. In this study we analyzed the expression levels of CXCL10 mRNA in the 90 chronic HCV patients using quantitative PCR (qPCR) prior, after, and during therapy with sofosbuvir/ribavirin (SOF+RBV) and sofosbuvir/daclatasvir/ribavirin (SOF+DCV+RBV), and further, the results were analyzed relative to treatment response. Significantly elevated CXCL10 mRNA was seen in naive patients having higher viral load (P = 0.005) and those suffering from hepatocellular carcinoma (P = 0.006). HCV patients had remarkable decline in CXCL10 level after 4, 12, and 24 weeks of therapy with DAAs. An approximate one-fold decrease was observed in patients who attained sustained virological response compared to untreated patients (P < 0.0001). Comparing the 2 regimens, the reduction in peripheral CXCL10 expression was more pronounced in patients undergoing SOF+DCV+RBV therapy. The current study implicitly shows the role of CXCL10 as an indicator of disruption of host-virus equilibrium and consequent pathogenesis of HCV during successful antiviral therapy. Furthermore, the drop in CXCL10 level after HCV viral clearance might reflect the DAA-induced alleviation in the extrahepatic manifestation of this infection.
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Affiliation(s)
- Maira Afzal
- Molecular Virology Laboratory, Centre for Applied Molecular Biology (CAMB), University of the Punjab, Lahore, Pakistan
| | - Amjad Ali
- Department of Genetics, Hazara University Mansehra, Khyber Pakhtunkhwa, Pakistan
| | - Nadeem Sheikh
- Department of Zoology, University of the Punjab, Lahore, Pakistan
| | - Shazia Rafique
- Divison of Molecular Virology, Center of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan
| | - Muhammad Idrees
- Divison of Molecular Virology, Center of Excellence in Molecular Biology (CEMB), University of the Punjab, Lahore, Pakistan
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11
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Grzegorzewska AE, Świderska MK, Marcinkowski W, Mostowska A, Jagodziński PP. Polymorphism rs368234815 of interferon-λ4 gene and generation of antibodies to hepatitis B virus surface antigen in extracorporeal dialysis patients. Expert Rev Vaccines 2020; 19:293-303. [PMID: 32228249 DOI: 10.1080/14760584.2020.1745637] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Background: The rs368234815 polymorphism of interferon-λ4 (IFN-λ4) gene (IFNL4) is involved in HBV surface antigen (HBsAg) clearance in non-uremic subjects. The rs368234815 ΔG/ΔG genotype can express IFN-λ4 while the TT/TT genotype cannot. We investigated whether rs368234815 is associated with the development of HBsAg antibodies (anti-HBs) in response to vaccination or infection, and HBsAg loss after infection in uremic patients on extracorporeal dialysis.Research design and methods: Dialyzed patients (n = 467) were genotyped for rs368234815 by the polymerase chain reaction-restriction fragment length polymorphism method. Non-responders to HBV vaccination we compared with responders. HBsAg positive patients not able to develop anti-HBs we compared with individuals who eliminated HBsAg and generated anti-HBs. HBsAg positive patients we compared with subjects who eliminated HBsAg.Results: The ∆G allele was associated with the 1.6-fold higher risk not to develop anti-HBs titers ≥10 IU/L in response to HBV vaccination and infection (P = 0.016 adjusted for gender, age at dialysis onset, HCV RNA). The ∆G/∆G genotype indicated a higher probability of non-responsiveness to HBV vaccination than the TT/TT genotype (OR 2.64, 95%CI 1.01-6.87, adjusted P = 0.048).Conclusions: In extracorporeal dialysis patients, IFNL4 rs368234815 is associated with the capacity to produce protective anti-HBs titers in response to HBV vaccination.
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Affiliation(s)
- Alicja E Grzegorzewska
- Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznań, Poland
| | - Monika K Świderska
- Department of Nephrology, Transplantology and Internal Diseases, Poznan University of Medical Sciences, Poznań, Poland
| | | | - Adrianna Mostowska
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań, Poland
| | - Paweł P Jagodziński
- Department of Biochemistry and Molecular Biology, Poznan University of Medical Sciences, Poznań, Poland
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12
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Tabll AA, Afifi MS, El-Etrawy AAS, El-Kousy SM, Smolic M, El Abd YS. CXCL9 chemokine level is associated with spontaneous clearance and sustained virological response in Egyptian Chronic Hepatitis C patients receiving direct acting antivirals. Hum Antibodies 2020; 28:141-148. [PMID: 32675406 DOI: 10.3233/hab-190400] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Chronic Hepatitis C virus (HCV) infection is associated with progressive liver inflammation which in turn leads to cirrhosis and finally causes hepatocellular carcinoma (HCC). By different escape mechanisms, the virus succeeds to evade the innate and acquired immune responses to establish chronic infection. AIM This study aimed to evaluate the level of chemokine CXCL9 and its correlation with some biochemical parameters in different subjects of HCV patients. MATERIALS AND METHODS A total of 83 persons participated in this study including healthy subjects without both HCV antibodies and HCV RNA (22.9%), HCV treated responders accomplished SVR post treatment, with HCV antibodies and absence of HCV RNA (24.1%), spontaneous or natural clearance patients, with positive HCV antibodies and negative HCV RNA without treatment (26.5%) and chronic HCV-patients, with both positive HCV antibodies and HCV RNA with no treatment (26.5%). HCV RNA was quantitated by real time PCR and serum CXCL9 level was measured by ELISA commercial kit pre-coated with human MIG/CXCL9 antibody. Assessment of biochemical and hematological parameters was carried out. RESULTS Data showed that, the level of CXCL9 was significantly increased in chronic individuals (627.1 pg/ml) (P< 0.001) than spontaneous clearance (107.76 pg/ml) and responder subjects (117.28 pg/ml) (P⩽ 0.05). No correlation has been found between CXCL9 level and viral load. Furthermore, CXCL9 levels correlated variably with some biochemical and hematological parameters according to each subject. CONCLUSION Serum Chemokine CXCL9 level is associated with spontaneous clearance of HCV and response to HCV treatment, which may be identified as a predictive marker among HCV patients.
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Affiliation(s)
- Ashraf A Tabll
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division National Research Centre, Giza, Egypt
| | - Mamdouh S Afifi
- Chemistry Department, Faculty of Science, Menufia University, Menufia, Egypt
| | - Abd-Allah S El-Etrawy
- Chemistry Department, Basic Science Center and Pharmaceutical Organic Chemistry Department, College of Pharmaceutical Sciences and Drug Manufacturing, Misr University for Science and Technology, 6th October City, Egypt
| | - Salah M El-Kousy
- Chemistry Department, Faculty of Science, Menufia University, Menufia, Egypt
| | - Martina Smolic
- Department of Pharmacology, Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia
| | - Yasmine S El Abd
- Microbial Biotechnology Department, Genetic Engineering and Biotechnology Research Division National Research Centre, Giza, Egypt
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13
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Ferrari SM, Fallahi P, Ruffilli I, Elia G, Ragusa F, Paparo SR, Patrizio A, Mazzi V, Colaci M, Giuggioli D, Ferri C, Antonelli A. Immunomodulation of CXCL10 Secretion by Hepatitis C Virus: Could CXCL10 Be a Prognostic Marker of Chronic Hepatitis C? J Immunol Res 2019; 2019:5878960. [PMID: 31485460 PMCID: PMC6702819 DOI: 10.1155/2019/5878960] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 04/19/2019] [Accepted: 04/30/2019] [Indexed: 12/17/2022] Open
Abstract
Chemokine (C-X-C motif) ligand (CXCL)10 and other CXCR3 chemokines are involved in the pathogenesis of acute and "chronic hepatitis C virus (HCV) infection" (CHC). Here, we review the scientific literature about HCV and CXCL10. The combination of circulating CXCL10 and single nucleotide polymorphisms (SNPs) in IL-28B can identify patients with acute HCV infection most likely to undergo spontaneous HCV clearance and those in need of early antiviral therapy. In CHC, the HCV and intrahepatic interferon- (IFN-) γ drive a raised CXCL10 expression by sinusoidal endothelium and hepatocytes, thereby inducing the recruitment of CXCR3-expressing T cells into the liver; thus, CXCL10 plays an important role in the development of necroinflammation and fibrosis. Increased CXCL10 was significantly associated with the presence of active vasculitis in HCV-associated cryoglobulinemia, or with autoimmune thyroiditis in CHC. Pretreatment CXCL10 levels are predictive of early virological response and sustained virological response (SVR) to IFN-α and ribavirin and may be useful in the evaluation of candidates for therapy. The occurrence of SNPs adjacent to IL-28B (rs12979860, rs12980275, and rs8099917), and CXCL10 below 150 pg/mL, independently predicted the first phase viral decline and rapid virological response, which in turn independently predicted SVR. Directly acting antiviral agents-mediated clearance of HCV is associated with the loss of intrahepatic immune activation by IFN-α, associated by decreased levels of CXCL10. In conclusion, CXCL10 is an important marker of HCV clearance and successful therapy in CHC patients. Whether CXCL10 is a novel therapeutic target in CHC will be evaluated.
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Affiliation(s)
| | - Poupak Fallahi
- Department of Translational Research and of New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Ilaria Ruffilli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giusy Elia
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesca Ragusa
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Armando Patrizio
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Valeria Mazzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Michele Colaci
- Internal Medicine Unit, Cannizzaro Hospital, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Dilia Giuggioli
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Clodoveo Ferri
- Rheumatology Unit, Azienda Ospedaliero-Universitaria di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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14
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Winckler FC, Braz AMM, Silva VND, Golim MDA, Andrade VGD, Machado PEDA, Silveira LVDA, Silva GF. Influence of the inflammatory response on treatment of hepatitis C with triple therapy. Rev Soc Bras Med Trop 2019; 51:731-736. [PMID: 30517525 DOI: 10.1590/0037-8682-0137-2018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 09/13/2018] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Chronic hepatitis C is a leading cause of liver disease. Infection triggers an immediate immune response in the host that is mediated by humoral/cellular mechanisms. T cells respond to infection via secretion of cytokines, which inhibit or stimulate one another, leading to cytokine imbalance and ultimately affecting treatment. Studies using interferon (IFN) and ribavirin (RBV) showed that TCD8+ cells and cytokine levels are associated with sustainable virological response (SVR). However, studies that investigated the effects of triple therapy (TT) are limited. METHODS The study included hepatitis C virus (HCV)+ RNA, naives, genotype 1, ≥18 years, and advanced fibrosis (F≥3) patients. Samples were collected at baseline and after 12 weeks (W12) of TT. Six cytokines were analyzed by flow cytometry. RESULTS Of 31 patients, four were excluded (two deaths, one interrupted TT, and one F2 patient). Of the 27 remaining patients, 21 (78%) were cirrhotic. SVR was achieved in 63% of the patients. The patients had a mean age of 55.11 ± 10.03 years. Analyses at baseline showed that the chemokine CCL5/Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) (p=0.04) and interleukin (IL)-6 (p=0.02), which was associated with SVR. RANTES (p=0.04) and IL-8 (p=0.01) levels were associated with SVR at W12. CONCLUSIONS Similar to patterns observed during double therapy, IL-6, IL-8, and RANTES levels were associated with SVR in TT, indicating the potential role of interferon in immune response to hepatitis C virus.
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Affiliation(s)
- Fernanda Cristina Winckler
- Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brasil
| | - Aline Marcia Marques Braz
- Laboratório de Citometria de Fluxo, Hemocentro, Universidade Estadual Paulista, Botucatu, SP, Brasil
| | - Vanessa Nogueira da Silva
- Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brasil
| | - Marjorie de Assis Golim
- Laboratório de Citometria de Fluxo, Hemocentro, Universidade Estadual Paulista, Botucatu, SP, Brasil
| | - Vanessa Gutierrez de Andrade
- Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brasil
| | - Paulo Eduardo de Abreu Machado
- Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brasil.,Laboratório de Citometria de Fluxo, Hemocentro, Universidade Estadual Paulista, Botucatu, SP, Brasil
| | | | - Giovanni Faria Silva
- Departamento de Clínica Médica, Faculdade de Medicina de Botucatu, Universidade Estadual Paulista, Botucatu, SP, Brasil
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15
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Li H, Huang MH, Jiang JD, Peng ZG. Hepatitis C: From inflammatory pathogenesis to anti-inflammatory/hepatoprotective therapy. World J Gastroenterol 2018; 24:5297-5311. [PMID: 30598575 PMCID: PMC6305530 DOI: 10.3748/wjg.v24.i47.5297] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Revised: 11/27/2018] [Accepted: 12/01/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection commonly causes progressive liver diseases that deteriorate from chronic inflammation to fibrosis, cirrhosis and even to hepatocellular carcinoma. A long-term, persistent and uncontrolled inflammatory response is a hallmark of these diseases and further leads to hepatic injury and more severe disease progression. The levels of inflammatory cytokines and chemokines change with the states of infection and treatment, and therefore, they may serve as candidate biomarkers for disease progression and therapeutic effects. The mechanisms of HCV-induced inflammation involve classic pathogen pattern recognition, inflammasome activation, intrahepatic inflammatory cascade response, and oxidative and endoplasmic reticulum stress. Direct-acting antivirals (DAAs) are the first-choice therapy for effectively eliminating HCV, but DAAs alone are not sufficient to block the uncontrolled inflammation and severe liver injury in HCV-infected individuals. Some patients who achieve a sustained virologic response after DAA therapy are still at a long-term risk for progression to liver cirrhosis and hepatocellular carcinoma. Therefore, coupling with anti-inflammatory/hepatoprotective agents with anti-HCV effects is a promising therapeutic regimen for these patients during or after treatment with DAAs. In this review, we discuss the relationship between inflammatory mediators and HCV infection, summarize the mechanisms of HCV-induced inflammation, and describe the potential roles of anti-inflammatory/hepatoprotective drugs with anti-HCV activity in the treatment of advanced HCV infection.
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Affiliation(s)
- Hu Li
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Meng-Hao Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Jian-Dong Jiang
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zong-Gen Peng
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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16
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Seshachalam VP, Sekar K, Hui KM. Insights into the etiology-associated gene regulatory networks in hepatocellular carcinoma from The Cancer Genome Atlas. J Gastroenterol Hepatol 2018; 33:2037-2047. [PMID: 29672926 DOI: 10.1111/jgh.14262] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIM Hepatitis B virus (HBV), hepatitis C virus, alcohol consumption, and non-alcoholic fatty liver disease are the major known risk factors for hepatocellular carcinoma (HCC). There have been very few studies comparing the underlying biological mechanisms associated with the different etiologies of HCC. In this study, we hypothesized the existence of different regulatory networks associated with different liver disease etiologies involved in hepatocarcinogenesis. METHODS Using upstream regulatory analysis tool in ingenuity pathway analysis software, upstream regulators (URs) were predicted using differential expressed genes for HCC to facilitate the interrogation of global gene regulation. RESULTS Analysis of regulatory networks for HBV HCC revealed E2F1 as activated UR, regulating genes involved in cell cycle and DNA replication, and HNF4A and HNF1A as inhibited UR. In hepatitis C virus HCC, interferon-γ, involved in cellular movement and signaling, was activated, while IL1RN, mitogen-activated protein kinase 1 involved in interleukin 22 signaling and immune response, was inhibited. In alcohol consumption HCC, ERBB2 involved in inflammatory response and cellular movement was activated, whereas HNF4A and NUPR1 were inhibited. For HCC derived from non-alcoholic fatty liver disease, miR-1249-5p was activated, and NUPR1 involved in cell cycle and apoptosis was inhibited. The prognostic value of representative genes identified in the regulatory networks for HBV HCC can be further validated by an independent HBV HCC dataset established in our laboratory with survival data. CONCLUSIONS Our study identified functionally distinct candidate URs for HCC developed from different etiologic risk factors. Further functional validation studies of these regulatory networks could facilitate the management of HCC towards personalized medicine.
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Affiliation(s)
| | - Karthik Sekar
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore
| | - Kam M Hui
- Laboratory of Cancer Genomics, Division of Cellular and Molecular Research, National Cancer Center Singapore, Singapore.,Institute of Molecular and Cell Biology, A*STAR, Singapore.,Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.,Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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17
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Venuto CS, Talal AH. Intrahepatic Sampling for the Elucidation of Antiviral Clinical Pharmacology. Clin Pharmacol Drug Dev 2018; 6:169-175. [PMID: 28263459 DOI: 10.1002/cpdd.311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 09/15/2016] [Indexed: 12/17/2022]
Abstract
Although the importance of the liver in clinical pharmacology is widely recognized, little is known in humans concerning its function in vivo at the hepatocyte level and how pharmacological functions are altered in the setting of advanced liver disease. Several recent proof-of-principle studies with first-generation DAAs have demonstrated the feasibility of serial liver sampling for pharmacological studies. These studies have begun to describe the liver-to-plasma concentration ratio and how this ratio is altered in the setting of advanced liver disease. These data are particularly relevant to individuals with substance-use disorders because many have advanced liver disease as a consequence of long-standing viral hepatitis infection or continued use of hepatotoxins such as alcohol. Future research should attempt to develop standardized and reproducible methods to assess liver drug concentration, complex drug interactions, and pharmacogenomics in humans to permit elucidation of the clinical pharmacology within the liver.
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Affiliation(s)
- Charles S Venuto
- Center for Human Experimental Therapeutics, University of Rochester, Rochester, NY, USA.,AIDS Clinical Trials Group Pharmacology Specialty Laboratory, New York State Center of Excellence in Bioinformatics and Life Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Andrew H Talal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University at Buffalo, Buffalo, NY, USA
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18
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Crisan D, Grigorescu MD, Radu C, Suciu A, Grigorescu M. Interferon-γ-inducible protein-10 in chronic hepatitis C: Correlations with insulin resistance, histological features & sustained virological response. Indian J Med Res 2018; 145:543-550. [PMID: 28862188 PMCID: PMC5663170 DOI: 10.4103/ijmr.ijmr_1410_14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND & OBJECTIVES One of the multiple factors contributing to virological response in chronic hepatitis C (CHC) is interferon-gamma-inducible protein-10 (IP-10). Its level reflects the status of interferon-stimulated genes, which in turn is associated with virological response to antiviral therapy. The aim of this study was to evaluate the role of serum IP-10 levels on sustained virological response (SVR) and the association of this parameter with insulin resistance (IR) and liver histology. METHODS Two hundred and three consecutive biopsy proven CHC patients were included in the study. Serum levels of IP-10 were determined using ELISA method. IR was evaluated by homeostasis model assessment-IR (HOMA-IR). Histological features were assessed invasively by liver biopsy and noninvasively using FibroTest, ActiTest and SteatoTest. Predictive factors for SVR and their interrelations were assessed. RESULTS A cut-off value for IP-10 of 392 pg/ml was obtained to discriminate between responders and non-responders. SVR was obtained in 107 patients (52.70%). Area under the receiver operating characteristic curve for SVR was 0.875 with a sensitivity of 91.6 per cent, specificity 74.7 per cent, positive predictive value 80.3 per cent and negative predictive value 88.7 per cent. Higher values of IP-10 were associated with increasing stages of fibrosis (P<0.01) and higher grades of inflammation (P=0.02, P=0.07) assessed morphologically and noninvasively through FibroTest and ActiTest. Significant steatosis and IR were also associated with increased levels of IP-10 (P=0.01 and P=0.02). In multivariate analysis, IP-10 levels and fibrosis stages were independently associated with SVR. INTERPRETATION & CONCLUSIONS Our findings showed that the assessment of serum IP-10 level could be a predictive factor for SVR and it was associated with fibrosis, necroinflammatory activity, significant steatosis and IR in patients with chronic HCV infection.
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Affiliation(s)
- Dana Crisan
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
| | - Mircea Dan Grigorescu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor", Cluj-Napoca, Romania
| | - Corina Radu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
| | - Alina Suciu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
| | - Mircea Grigorescu
- Department of Hepatology, Regional Institute of Gastroenterology & Hepatology "Prof. Dr. Octavian Fodor"; Department of Internal Medicine, 3rd Medical Clinic, Iuliu Hatieganu University of Medicine & Pharmacy, Cluj-Napoca, Romania
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19
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Lin CC, Su SH, Jeng WJ, Huang CH, Teng W, Chen WT, Chen YC, Lin CY, Sheen IS. CCL4 is the only predictor for non-responder in GT-1 CHC patients with favorable IL28B genotype when treated with PegIFN/RBV. BMC Gastroenterol 2017; 17:169. [PMID: 29284412 PMCID: PMC5747242 DOI: 10.1186/s12876-017-0724-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2016] [Accepted: 12/05/2017] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Chemokines/cytokines play important roles in the pathogenesis of chronic hepatitis C (CHC). However, their clinical characteristics and implications in treatment responses to pegylated interferon plus ribavirin treatment (PegIFN/RBV) have not been fully illustrated yet. In this study, we intended to investigate the possible predictability of serum chemokines/cytokines on the treatment response in Taiwanese of CHC, genotype-1 (GT-1). METHODS 60 Patients with GT-1 CHC infection who had been treated with PegIFN/RBV were enrolled, including 27 (45%) with sustained virological response (SVR), 11 (18%) with relapse after 48 weeks of treatment and 22 (37%) non-response (NR). Clinical parameters, seven chemokines/cytokines, CCL3, CCL4, CXCL9, CXCL10, CXCL11, IL-10 and IFN-γ, and genotypes of rs12979860, the single nucleotide polymorphisms (SNPs) of interleukin-28B (IL28B) were analyzed for their relationship to treatment response. RESULTS Baseline serum levels of CXCL10, CXCL11, CCL3 and CCL4 were significantly higher in NR group while comparing with non-NR group. (CXCL10: p = 0.001; CXCL11: p < 0.001; CCL3: p = 0.006; CCL4: p = 0.005). However, only rs12979860 CC genotype was the independent factors for NR in GT-1 CHC infection (OR, 8.985; p = 0.008). In addition, baseline serum level of CCL4 was found to be the only independent factor for NR in GT-1 CHC patients with favorable IL28B genotype (OR, 1.134; p = 0.039). CONCLUSIONS IL28B genotype is the predictor for NR in GT-1 CHC patients treated with PegIFN/RBV, while baseline serum level of CCL4 is the only predictor for NR in GT-1 CHC patients with favorable IL28B genotype.
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Affiliation(s)
- Chia-Chen Lin
- School of Medicine, College of Medicine, Chang-Gung University, 5, Fu-Xin street, Quain San, TaoYuan, 330 Taiwan
| | - Shih-Huan Su
- School of Medicine, College of Medicine, Chang-Gung University, 5, Fu-Xin street, Quain San, TaoYuan, 330 Taiwan
| | - Wen-Juei Jeng
- Division of Hepatology, Department of HepatoGastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, TaoYuan, Taiwan
| | - Chien-Hao Huang
- Division of Hepatology, Department of HepatoGastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, TaoYuan, Taiwan
| | - Wei Teng
- Division of Hepatology, Department of HepatoGastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, TaoYuan, Taiwan
| | - Wei-Ting Chen
- Division of Hepatology, Department of HepatoGastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, TaoYuan, Taiwan
| | - Yi-Cheng Chen
- School of Medicine, College of Medicine, Chang-Gung University, 5, Fu-Xin street, Quain San, TaoYuan, 330 Taiwan
- Division of Hepatology, Department of HepatoGastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, TaoYuan, Taiwan
| | - Chun-Yen Lin
- School of Medicine, College of Medicine, Chang-Gung University, 5, Fu-Xin street, Quain San, TaoYuan, 330 Taiwan
- Division of Hepatology, Department of HepatoGastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, TaoYuan, Taiwan
| | - I-Shyan Sheen
- School of Medicine, College of Medicine, Chang-Gung University, 5, Fu-Xin street, Quain San, TaoYuan, 330 Taiwan
- Division of Hepatology, Department of HepatoGastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, TaoYuan, Taiwan
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Laidlaw SM, Marukian S, Gilmore RH, Cashman SB, Nechyporuk-Zloy V, Rice CM, Dustin LB. Tumor Necrosis Factor Inhibits Spread of Hepatitis C Virus Among Liver Cells, Independent From Interferons. Gastroenterology 2017; 153:566-578.e5. [PMID: 28456632 PMCID: PMC5627365 DOI: 10.1053/j.gastro.2017.04.021] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Revised: 04/11/2017] [Accepted: 04/21/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Tumor necrosis factor (TNF) is an inflammatory cytokine expressed by human fetal liver cells (HFLCs) after infection with cell culture-derived hepatitis C virus (HCV). TNF has been reported to increase entry of HCV pseudoparticles into hepatoma cells and inhibit signaling by interferon alpha (IFNα), but have no effect on HCV-RNA replication. We investigated the effects of TNF on HCV infection of and spread among Huh-7 hepatoma cells and primary HFLCs. METHODS Human hepatoma (Huh-7 and Huh-7.5) and primary HFLCs were incubated with TNF and/or recombinant IFNA2A, IFNB, IFNL1, and IFNL2 before or during HCV infection. We used 2 fully infectious HCV chimeric viruses of genotype 2A in these studies: J6/JFH (clone 2) and Jc1(p7-nsGluc2A) (Jc1G), which encodes a secreted luciferase reporter. We measured HCV replication, entry, spread, production, and release in hepatoma cells and HFLCs. RESULTS TNF inhibited completion of the HCV infectious cycle in hepatoma cells and HFLCs in a dose-dependent and time-dependent manner. This inhibition required TNF binding to its receptor. Inhibition was independent of IFNα, IFNβ, IFNL1, IFNL2, or Janus kinase signaling via signal transducer and activator of transcription. TNF reduced production of infectious viral particles by Huh-7 and HFLC, and thereby reduced the number of infected cells and focus size. TNF had little effect on HCV replicons and increased entry of HCV pseudoparticles. When cells were incubated with TNF before infection, the subsequent antiviral effects of IFNs were increased. CONCLUSIONS In a cell culture system, we found TNF to have antiviral effects independently of, as well as in combination with, IFNs. TNF inhibits HCV infection despite increased HCV envelope glycoprotein-mediated infection of liver cells. These findings contradict those from other studies, which have reported that TNF blocks signal transduction in response to IFNs. The destructive inflammatory effects of TNF must be considered along with its antiviral effects.
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Affiliation(s)
- Stephen M. Laidlaw
- Kennedy Institute of Rheumatology, The University of Oxford, Oxford,
UK,Peter Medawar Building for Pathogen Research, The University of
Oxford, Oxford, UK
| | - Svetlana Marukian
- Laboratory of Virology and Infectious Disease, The Rockefeller
University, New York, NY, USA
| | - Rachel H. Gilmore
- Laboratory of Virology and Infectious Disease, The Rockefeller
University, New York, NY, USA
| | - Siobhán B. Cashman
- Kennedy Institute of Rheumatology, The University of Oxford, Oxford,
UK,Peter Medawar Building for Pathogen Research, The University of
Oxford, Oxford, UK
| | | | - Charles M. Rice
- Laboratory of Virology and Infectious Disease, The Rockefeller
University, New York, NY, USA
| | - Lynn B. Dustin
- Kennedy Institute of Rheumatology, The University of Oxford, Oxford,
UK,Peter Medawar Building for Pathogen Research, The University of
Oxford, Oxford, UK,Laboratory of Virology and Infectious Disease, The Rockefeller
University, New York, NY, USA,Corresponding author:
, Peter Medawar Building for
Pathogen Research, South Parks Road, Oxford, OX1 3SY, UK
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21
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Neesgaard B, Ruhwald M, Weis N. Inducible protein-10 as a predictive marker of antiviral hepatitis C treatment: A systematic review. World J Hepatol 2017; 9:677-688. [PMID: 28588752 PMCID: PMC5437612 DOI: 10.4254/wjh.v9.i14.677] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 12/30/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate interferon-γ-inducible protein-10’s (IP-10) potential to anticipate rapid (RVR)- and sustained virological responses (SVR) to chronic hepatitis C (CHC) treatment.
METHODS We included case series examining RVR or SVR in relation to 24 or 48 wk treatment for CHC, in patients treatment free for at least six months, with genotype 1 or 4, and in relation to 24 wk treatment for genotype 2 and 3, with pegylated interferon in combination with ribavirin. Patients had to have both a baseline IP-10 level as well as a hepatitis C virus (HCV)-RNA determination 4 wk after treatment initiation or 24 wk after end of treatment. Studies including patients with liver diseases other than CHC, human immunodeficiency virus-infection, treatment with immunosuppresents or cytostatica, alcohol dependency or active intravenous drug-use were excluded. We found 81 articles by searching the MEDLINE and EMBASE databases. Eight studies were eligible for inclusion. Their quality were assesed using an 18 point checklist for case series, developed using a modified Delphi technique. Information was extracted from the articles, and no raw data was requisitioned. The review protocol was registered at the International Prospective Register of Systematic Reviews (reg. number: CRD42014008736).
RESULTS Three studies reported on baseline IP-10 level in association with RVR. A signigficant association was found for HCV genotype 1 infection by two studies. Only two studies reported on HCV genotype 4 infected and genotype 2 and 3 infected patients, respectively. A trend was seen for an association between RVR and baseline IP-10 for genotype 4, while no association was found for genotype 2 and 3. Seven studies provided information regarding baseline IP-10 and SVR. Following the pattern regarding rapid virological response all five studies examining SVR in relation to baseline IP-10 levels for HCV, genotype 1 infected patients showed a significant association. Likewise a significant association was seen for HCV, genotype 4 infected, while no association was found for HCV, genotype 2 and 3 infected. Though only two studies examined the assosiation for HCV genotype 4 infected and HCV genotype 2 and 3 infected respectively.
CONCLUSION We found indications of a possible association between baseline IP-10 level and virological responses in patients with CHC genotype 1 and 4.
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22
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Lin WHW, Nelson AN, Ryon JJ, Moss WJ, Griffin DE. Plasma Cytokines and Chemokines in Zambian Children With Measles: Innate Responses and Association With HIV-1 Coinfection and In-Hospital Mortality. J Infect Dis 2017; 215:830-839. [PMID: 28119485 PMCID: PMC5388292 DOI: 10.1093/infdis/jix012] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 01/05/2017] [Indexed: 12/19/2022] Open
Abstract
To identify immune factors present during the acute rash phase of measles and associations with outcome and human immunodeficiency virus type 1 (HIV-1) coinfection, we measured the plasma levels of 22 cytokines and chemokines in Zambian children hospitalized with measles (n = 148) and control children (n = 44). Children with measles had higher levels of innate cytokines tumor necrosis factor (TNF) α, interleukin 1β (IL-1β), interleukin 18, and interleukin 6; chemokines CCL2, CCL4, CCL11, CCL22, CXCL8, and CXCL10; and T-cell cytokines interferon γ, and interleukin 2, 10, and 17. Children who died in the hospital had higher levels of TNF-α, IL-1β, interleukin 12p70; CCL2, CCL4, CCL13, CCL17, CXCL8, CXCL10; and interleukin 2 and interferon γ than children who survived, and lower levels of interleukin 4. Children coinfected with HIV-1 had higher levels of TNF-α and IL-1β than HIV-uninfected children with measles, and lower levels of interleukin 4 and 5. Therefore, acute measles was characterized by activation of macrophages and T cells producing type 1, but not type 2, cytokines, which was more pronounced in fatal disease.
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Affiliation(s)
- Wen-Hsuan W Lin
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
| | - Ashley N Nelson
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
| | - Judith J Ryon
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
| | - William J Moss
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Diane E Griffin
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, Baltimore, Maryland, USA
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23
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Chen M, Yao Y, Yue M, Zang F, Liu M, Wang J, Chen H, Zhang Y, Li J, Huang P, Yu R. Polymorphisms of chemokine receptor genes and clearance of hepatitis C virus infection in Chinese population. Gene 2017; 624:1-5. [PMID: 28456591 DOI: 10.1016/j.gene.2017.04.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/19/2017] [Accepted: 04/25/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND Chemokine genes play an essential role in both spontaneous clearance in acute infection and therapy of HCV. We investigated whether several CXC family-related genes associated with HCV spontaneous clearance and response to treatment. METHODS The current study genotyped four SNPs, respectively are CXCR6 rs2234358, CXCL12 rs1801157, CXCL9 rs10336, rs3733236 to assess their associations with HCV spontaneous clearance and response to treatment in a two stage study (668 chronic and 400 resolvers in discovery group, meanwhile 333 chronic and 199 resolver in replication group), and a treatment cohort of HCV with 282 patients. RESULTS We found that the CXCR6 rs2234358 was associated with HCV spontaneous clearance in Chinese Han population (dominant model: adjusted OR=1.62, 95%CI: 1.30-2.01; additive model: adjusted OR=1.43, 95%CI: 1.20-1.70). Patients carrying GT/TT genotypes had increased sustained virological response compared with patients carrying the GG genotype (dominant model: adjusted OR=2.23, 95%CI: 1.26-3.95). CONCLUSION These results suggest that CXCR6 rs2234358 is associated with spontaneous clearance of HCV and response to IFN-α/RBV therapy, which may be identified as a predictive marker in Chinese Han population of HCV.
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Affiliation(s)
- Mingzhu Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Yinan Yao
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Ming Yue
- Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Feng Zang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Mei Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China
| | - Jie Wang
- Department of Basic and Community Nursing, School of Nursing, Nanjing Medical University, Nanjing 211166, China
| | - Hongbo Chen
- Department of Infectious Diseases, the Jurong Peoples' Hospital, Jurong 212400, China
| | - Yun Zhang
- Institute of Epidemiology and Microbiology, Huadong Research Institute for Medicine and Biotechnics, Nanjing 210002, China
| | - Jun Li
- Department of Infectious Diseases, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Peng Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
| | - Rongbin Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 211166, China.
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24
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Chowdhury R, Tsen A. Recurrent Mixed Cryoglobulinemia Despite Sustained Virologic Response to Treatment: A Case Report. Am J Kidney Dis 2017; 70:301-304. [PMID: 28343737 DOI: 10.1053/j.ajkd.2017.01.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 01/03/2017] [Indexed: 01/01/2023]
Abstract
Cryoglobulinemia is a manifestation of hepatitis C virus (HCV) infection. Treatment of HCV is the mainstay of therapy for mixed cryoglobulinemia syndrome, and newer HCV therapies with direct-acting antiviral agents have achieved great success in treating HCV infection compared with pegylated interferon alfa and ribavirin. Recurrence of mixed cryoglobulinemia syndrome following successful treatment with direct-acting antiviral agents is uncommon, and when it occurs, it is most often due to relapse of HCV viremia. We report a case of recurrent mixed cryoglobulinemia syndrome following HCV treatment with a new direct-acting antiviral agent (sofosbuvir) and ribavirin, in which HCV RNA was undetectable in serum, but detectable in the cryoprecipitate.
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Affiliation(s)
| | - Adrianne Tsen
- University of Texas Health Science Center at San Antonio, San Antonio, TX.
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25
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Zhang M, Jiang Y, Xiao X, Peng M, Peng F, Gong G. Differences in IP‑10, TLR4 and IRF5/3 between SVR and non‑SVR HCV‑1 patients treated with PEG‑IFN and ribavirin. Mol Med Rep 2017; 15:2318-2324. [PMID: 28259968 DOI: 10.3892/mmr.2017.6229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 11/01/2016] [Indexed: 11/06/2022] Open
Abstract
The present study aimed to investigate alterations in Toll‑like receptor 4 (TLR4), interferon regulatory factor 5 (IRF5) and interferon‑γ‑inducible protein‑10 (IP‑10), and evaluate whether these factors may be associated with a sustained virological response (SVR) among patients with hepatitis C virus genotype‑1 (HCV‑1) who were treated with peginterferon plus ribavirin (PEG‑IFN‑RBV). A total of 31 Chinese patients infected with HCV‑1 were enrolled in the present study and 25 patients obtained SVR. The expression levels of IP‑10 declined significantly during PEG‑IFN‑RBV therapy at the 24 and 48 week time‑points, compared with the baseline (P<0.005, 0.001 and 0.001, respectively). In addition, it was observed that IRF5 mRNA expression and the number of TLR4+ peripheral blood mononuclear cells exhibited similar correlations with IP‑10 concentration (R2=0.0726, P=0.001, R2=0.1634, P<0.0001, respectively) in the SVR group patients; however, these correlations were not observed to be present in the non‑SVR group patients. In conclusion, the results of the present study suggest that marked alterations in IP‑10, TLR4 and IRF5 expression may serve as indicators for the development of SVR in patients with HCV‑1 treated with PEG‑IFN‑RBV.
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Affiliation(s)
- Min Zhang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yongfang Jiang
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Xinqiang Xiao
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Milin Peng
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Feng Peng
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Guozhong Gong
- Institute of Hepatology and Department of Infectious Diseases, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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26
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Yamagiwa Y, Asano M, Kawasaki Y, Korenaga M, Murata K, Kanto T, Mizokami M, Masaki N. Pretreatment serum levels of interferon-gamma-inducible protein-10 are associated with virologic response to telaprevir-based therapy. Cytokine 2016; 88:29-36. [PMID: 27541605 DOI: 10.1016/j.cyto.2016.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Revised: 07/03/2016] [Accepted: 07/05/2016] [Indexed: 01/16/2023]
Abstract
AIM Telaprevir (TVR) remarkably improves the efficacy of interferon treatment for chronic hepatitis C. Interleukin-28B (IL28B) genotype and interferon-gamma-inducible protein-10 (IP-10) level predict virologic response to peg-interferon (Peg-IFN)/ribavirin (RBV) therapy. We aimed to investigate the usefulness of pretreatment serum IP-10 levels and IL28B genotyping in predicting sustained virologic response (SVR) to TVR-based triple therapy. METHODS In this multi-center study, patients infected with hepatitis C virus genotype 1 with high viral load (⩾5.0logIU/mL) were treated with TVR for 12weeks and Peg-IFN/RBV for 24weeks in Japan. IL28B genotype, serum IP-10 levels, other clinical parameters, and drug dosages were assessed before treatment. RESULTS We included 121 patients who were treated with TVR for at least 8weeks and Peg-IFN/RBV for 24weeks. The median IP-10 levels were significantly lower in rapid virologic response (RVR) or SVR in the IL28B non-TT genotype group, with no significant difference in the TT genotype group. RVR rates were significantly lower in the group with higher serum IP-10 levels (>450pg/mL). In the non-TT IL28B genotype group, RVR and SVR rates were significantly lower in the group with higher IP-10 levels. SVR rates in the group with lower IP-10 levels (<450pg/mL) increased to 82% for those showing RVR, but reduced to 27% in the group with higher IP-10 levels for those not showing RVR. CONCLUSIONS Determination of serum IP-10 levels before treatment could be useful for predicting favorable virologic response to TVR-based triple therapy, especially in patients with IL28B non-TT genotype.
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Affiliation(s)
- Yoko Yamagiwa
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan.
| | - Mai Asano
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Youhei Kawasaki
- Department of Drug Evaluation & Informatics, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan
| | - Masaaki Korenaga
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Kazumoto Murata
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Tatsuya Kanto
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
| | - Naohiko Masaki
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan
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27
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Chen Yi Mei SLG, Burchell J, Skinner N, Millen R, Matthews G, Hellard M, Dore GJ, Desmond PV, Sundararajan V, Thompson AJ, Visvanathan K, Sasadeusz J. Toll-like Receptor Expression and Signaling in Peripheral Blood Mononuclear Cells Correlate With Clinical Outcomes in Acute Hepatitis C Virus Infection. J Infect Dis 2016; 214:739-47. [PMID: 27284092 DOI: 10.1093/infdis/jiw235] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 05/23/2016] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Mechanisms by which spontaneous clearance of acute hepatitis C occurs are unclear. A critical role for the innate immune system and IFNL4 polymorphisms has been proposed. This study investigates whether Toll-like receptor (TLR) expression and signaling during acute hepatitis C correlates with clinical outcomes. METHODS Participants identified from the Australian Trial in Acute Hepatitis C and the Networks study were followed longitudinally from the time of diagnosis of acute hepatitis C. Peripheral blood mononuclear cells (PBMCs) and plasma were collected at and 2 time points after diagnosis. At each time point, TLR2, TLR4, and CD86 expression on peripheral blood monocytes, natural killer (NK) cells, and NK T cells was measured, as well as the response of PBMCs to stimulation with TLR ligands. Cytokine and chemokine levels were measured in stimulated PBMCs and plasma. RESULTS We identified 20 participants with acute hepatitis C (10 with hepatitis C virus [HCV] monoinfection and 10 with HCV and human immunodeficiency virus coinfection). Eleven participants (55%) spontaneously cleared HCV. Acute hepatitis C and spontaneous clearance was associated with lower TLR4 expression on monocytes (P = .009) and NK cells (P = .029). Acute hepatitis C and spontaneous clearance was also associated with a reduced interferon γ response to TLR4 (P = .038) and TLR7/8 stimulation (P = .035), a reduced interleukin 6 response to TLR7/8 stimulation (P = .037), and reduced IFN-γ-inducible protein 10 (IP-10) response to TLR2 stimulation (P = .042). Lower plasma IP-10 levels were associated with spontaneous clearance (P = .001). CONCLUSIONS These findings implicate TLR4 signaling as playing a critical role in the outcome of acute hepatitis C.
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Affiliation(s)
- Swee Lin G Chen Yi Mei
- Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Jodie Burchell
- Centre of Research Excellence, Department of Medicine, St Vincent's Hospital, Melbourne
| | - Narelle Skinner
- Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Rosie Millen
- Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Gail Matthews
- Kirby Institute, University of New South Wales, Sydney
| | - Margaret Hellard
- Centre for Population Health, Burnet Institute Department of Infectious Diseases, the Alfred Hospital, Melbourne, Australia
| | | | | | - Vijaya Sundararajan
- Centre of Research Excellence, Department of Medicine, St Vincent's Hospital, Melbourne
| | - Alexander J Thompson
- Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Kumar Visvanathan
- Department of Gastroenterology, St Vincent's Hospital Immunology Research Centre, Department of Medicine, St Vincent's Hospital and the University of Melbourne
| | - Joe Sasadeusz
- Department of Infectious Diseases, Royal Melbourne Hospital
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Decalf J, Tarbell KV, Casrouge A, Price JD, Linder G, Mottez E, Sultanik P, Mallet V, Pol S, Duffy D, Albert ML. Inhibition of DPP4 activity in humans establishes its in vivo role in CXCL10 post-translational modification: prospective placebo-controlled clinical studies. EMBO Mol Med 2016; 8:679-83. [PMID: 27137491 PMCID: PMC4888857 DOI: 10.15252/emmm.201506145] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Biochemical experiments, animal models, and observational studies in humans all support a role of dipeptidyl peptidase 4 (DPP4) in the N‐terminal truncation of CXCL10, which results in the generation of an antagonist form of the chemokine that limits T‐cell and NK cell migration. Motivated by the ability to regulate lymphocyte trafficking in vivo, we conducted two prospective clinical trials to test the effects of DPP4 inhibition on CXCL10 processing in healthy donors and in chronic hepatitis C patients, a disease in which DPP4 levels are found to be elevated. Participants were treated daily with 100 mg sitagliptin, a clinically approved DPP4 inhibitor. Plasma samples were analyzed using an ultrasensitive single‐molecule assay (Simoa) to distinguish the full‐length CXCL101–77 from the NH2‐truncated CXCL103–77, as compared to the total CXCL10 levels. Sitagliptin treatment resulted in a significant decrease in CXCL103–77 concentration, a reciprocal increase in CXCL101–77, with only minimal effects on total levels of the chemokine. These data provide the first direct evidence that in vivo DPP4 inhibition in humans can preserve the bioactive form of CXCL10, offering new therapeutic opportunities for DPP4 inhibitors.
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Affiliation(s)
- Jérémie Decalf
- The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France
| | - Kristin V Tarbell
- Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Armanda Casrouge
- The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France
| | - Jeffrey D Price
- Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Grace Linder
- Diabetes Endocrinology and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Estelle Mottez
- Center for Human Immunology, Institut Pasteur, Paris, France
| | - Philippe Sultanik
- Département d'Hépatologie, AP-HP, Hôpital Cochin, Université Paris Descartes, INSERM UMS20, Institut Pasteur, Paris, France
| | - Vincent Mallet
- Département d'Hépatologie, AP-HP, Hôpital Cochin, Université Paris Descartes, INSERM UMS20, Institut Pasteur, Paris, France
| | - Stanislas Pol
- Département d'Hépatologie, AP-HP, Hôpital Cochin, Université Paris Descartes, INSERM UMS20, Institut Pasteur, Paris, France
| | - Darragh Duffy
- The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France Center for Human Immunology, Institut Pasteur, Paris, France
| | - Matthew L Albert
- The Laboratory of Dendritic Cell Immunobiology, Institut Pasteur, Paris, France INSERM U818, Paris, France Center for Human Immunology, Institut Pasteur, Paris, France Department of Cancer Immunotherapy, Genentech, South San Francisco, CA, USA
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29
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Zhang R, Shao C, Huo N, Li M, Xu X. Association of IL28B Genotypes and Baseline Serum Interferon-γ-Inducible- Protein-10 Levels with Treatment Response in Hepatitis C Virus Patients in China. Gut Liver 2016; 10:446-55. [PMID: 26470765 PMCID: PMC4849699 DOI: 10.5009/gnl15162] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 05/19/2015] [Accepted: 05/28/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND/AIMS Several studies have demonstrated that serum interferon-γ-inducible-protein-10 (IP-10) levels at baseline and single nucleotide polymorphisms (SNPs) near the IL28B gene were associated with viral response and treatment outcomes. Our purpose was to assess the combination of pretreatment IP-10 levels with IL28B SNPs as predictors of treatment response to pegylated interferon α-2a plus ribavirin in patients infected with genotype 1 hepatitis C virus in China. METHODS Seventy-two patients with chronic hepatitis C without fibrosis/cirrhosis were enrolled in the study. The virologic parameters and baseline serum IP-10 levels were determined. IL-28B genotypes were determined by sequencing. RESULTS In this cohort, serum baseline IP-10 levels lower than 426.7 pg/mL could predict rapid virological response/ sustained virological response (SVR). Patients carrying favorable IL28B SNP genotypes had higher SVRs than did those carrying unfavorable variants (IL28B rs12979860, p=0.002; IL28B rs8099917, p=0.020). Combining both baseline IP- 10 and IL28B SNPs could improve the prediction of SVR in favorable allele carriers of IL28B, rs12979860 CC and rs8099917 TT. Serum baseline IP-10 levels and IL28B genotypes were independent predictors of SVR. CONCLUSIONS Our study shows that the combination of baseline serum IP-10 levels and the determination of IL28B SNPs increase the predictability of SVR rates in this cohort. (Gut Liver 2016;10446-455).
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Affiliation(s)
- Renwen Zhang
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Cuiping Shao
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Na Huo
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Minran Li
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing,
China
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Lu MY, Huang CI, Dai CY, Wang SC, Hsieh MY, Hsieh MH, Liang PC, Lin YH, Hou NJ, Yeh ML, Huang CF, Lin ZY, Chen SC, Huang JF, Chuang WL, Yu ML. Elevated on-treatment levels of serum IFN-gamma is associated with treatment failure of peginterferon plus ribavirin therapy for chronic hepatitis C. Sci Rep 2016; 6:22995. [PMID: 26965318 PMCID: PMC4786849 DOI: 10.1038/srep22995] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 02/22/2016] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection had been associated with cytokine imbalance. Cytokine dynamics in response to peginterferon/ribavirin therapy have an impact on the treatment efficacy for HCV patients. Ninety-two treatment-naive chronic hepatitis C patients were treated with 24 or 48 weeks of peginterferon/ribavirin therapy according to their viral genotypes. Sustained virologic response (SVR) is defined as undetectable HCV RNA throughout a 24-week post-treatment follow-up period. Dynamic serum levels of the following cytokines: (1) Th1-mediated cytokines: IFN-γ, interleukin-2, and TNF-alpha; (2)Th2-mediated cytokines: interleukin-4, interleukin-5, interleukin-6, and interleukin-10 and (3)immuno-modulatory cytokines: interleukin-1β, interleukin-8, and interleukin-12 were determined by Fluorescent Bead immunoassay. Serial dynamic cytokine expression demonstrated that not only elevated IFN-γ concentrations at specific time points but also the total IFN-γ amount was strongly linked to non-response in peginterferon/ribavirin therapy. IFN-γ levels could serve as an independent predictor for SVR analyzed by multivariate logistic regression test. The accuracy of discriminating responders from non-responders was acceptable when IFN-γ cut-off levels were set at 180, 120, and 40 pg/ml at the 4th week, 12th week, and end-of-treatment of therapy, respectively. Elevated on-treatment IFN-γ concentration was significantly associated with treatment failure among interleukin-28B rs8099917TT carriers and those patients failed to achieve rapid virologic response.
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Affiliation(s)
- Ming-Ying Lu
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-I Huang
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Chi Wang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Ming-Yen Hsieh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Meng-Hsuan Hsieh
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Preventive Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Po-Cheng Liang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Yi-Hung Lin
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| | - Nai-Jen Hou
- Department of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Occupational Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zu-Yau Lin
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shinn-Cherng Chen
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
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Johansson S, Talloen W, Tuefferd M, Darling J, Fanning G, Fried MW, Aerssens J. High MIG (CXCL9) plasma levels favours response to peginterferon and ribavirin in HCV-infected patients regardless of DPP4 activity. Liver Int 2016; 36:344-52. [PMID: 26344576 PMCID: PMC4744814 DOI: 10.1111/liv.12932] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 07/22/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Sustained virological response (SVR) following peginterferon (pegIFN) and ribavirin (RBV) treatment in hepatitis C virus (HCV)-infected patients has been linked with the IL28B genotype and lower peripheral levels of the CXCR3-binding chemokine IP-10 (CXCL10). To further improve the understanding of these biomarkers we investigated plasma levels of the other CXCR3-binding chemokines and activity of the dipeptidyl peptidase IV (DPP4, CD26) protease, which cleaves IP-10, in relation to treatment response. METHODS African-American and Caucasian HCV genotype 1-infected patients (n = 401) were treated with pegIFN/RBV for 48 weeks (ViraHep-C cohort). Pretreatment plasma levels of MIG (CXCL9), I-TAC (CXCL11) and the type III interferon IL29 were investigated by Luminex and DPP4 activity by using a luciferase assay. RESULTS Patients achieving SVR had higher baseline MIG plasma levels and lower DPP4 activity than non-SVR patients. MIG was higher in Caucasians, IL28B CC (rs1297860) genotype carriers and patients with higher ALT levels. MIG correlated with IP-10 in SVR patients, but not in non-SVRs. A high DPP4 activity correlated with higher IP-10 levels, while DPP4 activity was not associated with MIG or I-TAC levels. CONCLUSIONS The associations of MIG with SVR status and IL28B genotype imply that higher MIG plasma levels could reflect a beneficial immunological state for response to pegIFN/RBV treatment. The correlation between MIG and IP-10 observed only in SVR patients may contribute to a better treatment response, whereas this MIG/IP-10 balance might be disrupted in non-SVR patients because of the increased DPP4 cleavage of IP-10 into a dysfunctional form.
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Affiliation(s)
| | | | | | - Jama Darling
- University of North Carolina, Chapel Hill, NC, USA
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Bartolomé J, Castillo I, Quiroga JA, Carreño V. Interleukin-28B polymorphisms and interferon gamma inducible protein-10 serum levels in seronegative occult hepatitis C virus infection. J Med Virol 2016; 88:268-74. [PMID: 26147900 DOI: 10.1002/jmv.24322] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2015] [Indexed: 12/31/2022]
Abstract
Polymorphisms upstream interleukin (IL)-28B gene and serum levels of interferon gamma inducible protein-10 (IP-10) are associated with spontaneous and treatment-induced hepatitis C virus (HCV) clearance. Patients with seronegative occult HCV infection are anti-HCV and serum HCV-RNA negative but have viral RNA in liver and abnormal values of liver enzymes. We examined if the rs12979860 polymorphism of IL-28B and serum IP-10 levels differ between chronic and seronegative occult CV infection. IL-28B polymorphism was determined with allele specific TaqMan probes in total DNA isolated from peripheral blood mononuclear cells and IP-10 by an enzyme-linked immunosorbent assay in serum from 99 patients with seronegative occult HCV infection and 130 untreated patients with chronic hepatitis C. IL-28B genotypes were also determined in 54 healthy volunteers. Prevalence of the IL-28B CC genotype was significantly higher in seronegative occult HCV infection (52/99; 52.5%) than in chronic hepatitis C (32/130; 24.6%, P < 0.0001) or healthy controls (19/54: 32.5%, P = 0.039). Among patients with seronegative occult HCV infection, HCV-RNA load in liver was significantly lower in those with the IL-28B CC genotype than in those with CT + TT genotypes (2.8 × 10(5) ± 5.8 × 10(4) vs. 4.1 × 10(5) ± 5.9 × 10(4) copies/μg of total RNA respectively; P = 0.023). Mean serum IP-10 levels were significantly lower in patients with seronegative occult HCV infection than in patients with chronic hepatitis C (160.8 ± 17.9 vs. 288.7 ± 13.3 pg/ml respectively; P < 0.0001). These findings suggest that the host immune response plays an important role in seronegative occult HCV infection in comparison with chronic hepatitis C.
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Affiliation(s)
- Javier Bartolomé
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
| | | | | | - Vicente Carreño
- Fundación para el Estudio de las Hepatitis Virales, Madrid, Spain
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Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, Steele D, Thiim M, Williams WW, Hashemi N, Kim AY, Thadhani R, Chung RT. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology 2016; 63:408-17. [PMID: 26474537 PMCID: PMC4718772 DOI: 10.1002/hep.28297] [Citation(s) in RCA: 180] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 10/12/2015] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events. CONCLUSION SVR12 rates for sofosbuvir-based DAA regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.
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Affiliation(s)
- Meghan E. Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Allyson K. Bloom
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital
| | - Jessica Wisocky
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
| | - Ming V. Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Brigham and Women’s Hospital
| | - Jenna L. Gustafson
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
| | - Andrew L. Lundquist
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - David Steele
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Michael Thiim
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
| | - Winfred W. Williams
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Nikroo Hashemi
- Division of Gastroenterology and Hepatology, Department of Medicine, Brigham and Women’s Hospital
| | - Arthur Y. Kim
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital
| | - Ravi Thadhani
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Raymond T. Chung
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
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Wong GLH, Chan HLY, Chan HY, Tse CH, Chim AML, Lo AOS, Wong VWS. Serum interferon-inducible protein 10 levels predict hepatitis B s antigen seroclearance in patients with chronic hepatitis B. Aliment Pharmacol Ther 2016; 43:145-53. [PMID: 26526395 DOI: 10.1111/apt.13447] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 09/08/2015] [Accepted: 10/06/2015] [Indexed: 12/15/2022]
Abstract
BACKGROUND Hepatitis B s antigen (HBsAg) seroclearance is regarded as the optimal virological end-point. AIM To investigate the dynamic changes in serum cytokine levels around the time of HBsAg seroclearance. METHODS This was a case-control study. Consecutive patients with chronic hepatitis B (CHB) who lost HBsAg were matched with those remained positive for HBsAg with same age, gender, HBeAg status and presence of cirrhosis in 1:2 ratio. Relevant serum cytokines [interleukin (IL)-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IL-15, IL-21 interferon-γ, tumour necrosis factor-α (TNF-α), granulocyte macrophage colony-stimulating factor (GM-CSF) and interferon-inducible protein 10 (IP-10)] were assayed at the time (Year 0) and 3 years before (Year -3) HBsAg seroclearance. RESULTS Seventy-one and 142 CHB patients who did and did not achieve HBsAg seroclearance were included. Mean age was 48 ± 11 years; 76% were male, 20% had positive HBeAg, 99 (46%) patients received anti-viral therapy, and mean baseline HBV DNA was 3.78 ± 2.28 log IU/mL vs. 4.36 ± 2.13 log IU/mL respectively (P = 0.05). In those who achieved HBsAg seroclearance, serum IL-15 and GM-CSF levels decreased significantly from Year -3 to Year 0 (P = 0.017 and 0.05 respectively). When compared to controls, only serum IP-10 level was significantly lower at Year 0 than at Year -3 in patients with HBsAg seroclearance. Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance. There was no correlation between serum IP-10 and HBsAg levels around the time of HBsAg seroclearance. CONCLUSION Lower serum IP-10 level at Year 0 was the only factor associated with HBsAg seroclearance.
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Affiliation(s)
- G L-H Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - H L-Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - H-Y Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - C-H Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
| | - A M-L Chim
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - A O-S Lo
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - V W-S Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong.,State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong
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35
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Jabłońska J, Pawłowski T, Laskus T, Zalewska M, Inglot M, Osowska S, Perlejewski K, Bukowska-Ośko I, Cortes KC, Pawełczyk A, Ząbek P, Radkowski M. The correlation between pretreatment cytokine expression patterns in peripheral blood mononuclear cells with chronic hepatitis C outcome. BMC Infect Dis 2015; 15:556. [PMID: 26637466 PMCID: PMC4670510 DOI: 10.1186/s12879-015-1305-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Accepted: 12/01/2015] [Indexed: 12/24/2022] Open
Abstract
Backgroud Cytokine response against hepatitis C virus (HCV) is likely to determine the natural course of infection as well as the outcome of antiviral treatment. However, the role of particular cytokines remains unclear. The current study analyzed activation of cytokine response in chronic hepatitis C patients undergoing standard antiviral treatment. Methods Twenty-two patients were treated with pegylated interferon and ribavirin. Twenty-six different cytokine transcripts were measured quantitatively in peripheral blood mononuclear cells (PBMC) before and after therapy and correlated with therapy outcome as well as with clinical and liver histological data. Results We found that patients who achieved sustained virological response (SVR) showed higher pretreatment cytokine response when compared to subjects in whom therapy was unsuccessful. The differentially expressed factors included IL-8, IL-16, TNF-α, GM-CSF, MCP-2, TGF-β, and IP-10. Serum ALT activity and/or histological grading also positively correlated with the expression of IL-1α, IL-4, IL-6, IL-10, IL-12, IL-15, GM-CSF, M-CSF, MCP-2 and TGF-β. Conclusion Pretreatment activation of the immune system, as reflected by cytokines transcripts upregulation, positively correlates with treatment outcome and closely reflects liver inflammatory activity.
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Affiliation(s)
- Joanna Jabłońska
- Department of Hepatology and Acquired Immunodeficiences, Medical University of Warsaw, Warsaw, Poland.
| | - Tomasz Pawłowski
- Division of Psychotherapy and Psychosomatic Medicine, Wrocław Medical University, Wrocław, Poland.
| | - Tomasz Laskus
- Department of Immunopathology of Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - Małgorzata Zalewska
- Department of Infectious Diseases, Hepatology and Acquired Immune Deficiences, Wrocław Medical University, Wrocław, Poland.
| | - Małgorzata Inglot
- Department of Infectious Diseases, Hepatology and Acquired Immune Deficiences, Wrocław Medical University, Wrocław, Poland.
| | - Sylwia Osowska
- Department of General Surgery and Clinical Nutrition, Medical University of Warsaw, Warsaw, Poland.
| | - Karol Perlejewski
- Department of Immunopathology of Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - Iwona Bukowska-Ośko
- Department of Immunopathology of Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - Kamila Caraballo Cortes
- Department of Immunopathology of Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - Agnieszka Pawełczyk
- Department of Immunopathology of Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
| | - Piotr Ząbek
- Municipal Hospital of Infectious Diseases, Warsaw, Poland.
| | - Marek Radkowski
- Department of Immunopathology of Infectious Diseases, Medical University of Warsaw, Warsaw, Poland.
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36
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Chemokine Receptors CXCR3 and CCR6 and Their Ligands in the Liver and Blood of Patients with Chronic Hepatitis C. Bull Exp Biol Med 2015; 160:252-5. [DOI: 10.1007/s10517-015-3142-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2014] [Indexed: 10/22/2022]
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Carlin AF, Aristizabal P, Song Q, Wang H, Paulson MS, Stamm LM, Schooley RT, Wyles DL. Temporal dynamics of inflammatory cytokines/chemokines during sofosbuvir and ribavirin therapy for genotype 2 and 3 hepatitis C infection. Hepatology 2015; 62:1047-58. [PMID: 26147061 PMCID: PMC4589477 DOI: 10.1002/hep.27971] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2015] [Accepted: 07/01/2015] [Indexed: 12/14/2022]
Abstract
UNLABELLED The analysis of inflammatory cytokines and chemokines produced during hepatitis C virus (HCV) infection has advanced our understanding of viral-host interactions and identified predictors of treatment response. Administration of interferons (IFNs) made it difficult to interpret biomarkers of immune activation during treatment. Direct-acting antiviral (DAA) regimens without IFN are now being used to treat HCV with excellent efficacy. To gain insight into HCV-host interactions occurring before, during, and after HCV treatment, we performed a case-control study that measured serial plasma levels of IFN-γ-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 beta (MIP-1β), and interleukin-18 (IL-18) in 131 patients with chronic HCV treated with sofosbuvir (SOF) plus ribavirin (RBV). A linear regression analysis using baseline factors identified strong positive associations between elevated alanine aminotransferase and pretreatment IP-10 and between the presence of cirrhosis and elevated pretreatment IL-18. Mean IP-10, MCP-1, MIP-1β, and IL-18 levels all decline on therapy, but display different dynamics late in treatment and after cessation of therapy. On treatment, IP-10 and MIP-1β levels were significantly higher in individuals who achieved sustained virological response (SVR). Logistic regression analyses examining treatment response in all patients demonstrated significant associations between higher baseline MIP-1β levels and smaller decreases in MIP-1β early in treatment and SVR. Higher early MIP-1β levels were also significantly associated with SVR in subsets of patients with cirrhosis and individuals with genotype 3 (GT3) infection, two factors associated with decreased responsiveness to treatment. CONCLUSION Changes in IP-10 levels mirror HCV RNA, suggesting that IP-10 is an indicator of innate immune viral recognition. MIP-1β levels remain elevated in GT2/3 patients who achieved SVR, suggesting differential immune activation in those who respond to SOF/RBV therapy and a potential role in predicting treatment responses.
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Affiliation(s)
- Aaron F Carlin
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - Paula Aristizabal
- Department of Pediatrics, University of California San Diego, La Jolla, CA
| | | | | | | | | | - Robert T Schooley
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - David L Wyles
- Department of Medicine, University of California San Diego, La Jolla, CA
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38
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Abstract
Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-γ-inducible CXC chemokine ligand (CXCL)9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases-mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes-are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-α may result in viral clearance during persistent infection and revert this process. Theoretically agents that selectively neutralize CXCL10 could increase patient responsiveness to traditional IFN-based HCV therapy. Several studies have reported IL-28B polymorphisms and circulating CXCL10 may be a prognostic markers for HCV treatment efficacy in HCV genotype 1 infection.
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Affiliation(s)
- Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, 56126, Pisa, Italy,
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39
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El Raziky M, Elsharkawy A, Said SE, Abdelatty S, El Akel W, Tantawy O, Gamal Eldeen H, Mabrouk M. IP-10 Serum Level in Chronic Hepatitis C Virus Patients: Relation to Fibrosis and Response to Combined Interferon/Ribavirin Therapy. J Interferon Cytokine Res 2015; 35:649-53. [PMID: 25973761 DOI: 10.1089/jir.2014.0193] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Despite the appearance of the direct acting antiviral drugs, pegylated interferon/ribavirin (PEG-IFN/RBV) still has a place in the standard of care (SOC) therapy for chronic HCV4. Studies were conducted to find an accurate prediction in response to SOC therapy. Pretreatment serum interferon-γ-inducible protein-10 (IP-10) is an independent predictive factor of sustained virological response (SVR) in HCV1-infected patients. To assess whether the pretreatment serum level of IP-10 influences hepatic fibrosis and PEG-IFN/RBV therapy response, a study was conducted on 88 chronic Hepatitis C virus (HCV) patients who received PEG-IFN/RBV. Patients were subjected to a pretreatment routine laboratory evaluation, liver biopsy, and serum IP-10 assessment. They were followed up for 6 months after cessation of therapy (week 72). Patients were classified into 3 groups according to their response; nonresponders, relapsers, or sustained virological responders. The relation of pretreatment IP-10 with fibrosis and response was assessed. The studied groups were matched regarding their demographic data. There was no statistically significant association between the pretreatment IP-10 level and fibrosis (P=0.86) and no relation to response was found at week 12, 24, 48, and 72 (P=0.58, 0.8, 0.47, and 0.43, respectively). Pretreatment IP-10 could not predict either fibrosis or response to PEG-IFN/RIB therapy in chronic HCV Egyptian patients.
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Affiliation(s)
- Maissa El Raziky
- 1 Department of Endemic Hepatology and Gasteroenterology, Cairo University , Cairo, Egypt
| | - Aisha Elsharkawy
- 1 Department of Endemic Hepatology and Gasteroenterology, Cairo University , Cairo, Egypt
| | - Salma E Said
- 2 Department of Biochemistry, Cairo University , Cairo, Egypt
| | - Sahar Abdelatty
- 3 Department of Chemical and Clinical Pathology, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Wafaa El Akel
- 1 Department of Endemic Hepatology and Gasteroenterology, Cairo University , Cairo, Egypt
| | - Omnia Tantawy
- 1 Department of Endemic Hepatology and Gasteroenterology, Cairo University , Cairo, Egypt
| | - Hadeel Gamal Eldeen
- 1 Department of Endemic Hepatology and Gasteroenterology, Cairo University , Cairo, Egypt
| | - Mahasen Mabrouk
- 1 Department of Endemic Hepatology and Gasteroenterology, Cairo University , Cairo, Egypt
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Gragnani L, Fognani E, Piluso A, Boldrini B, Urraro T, Fabbrizzi A, Stasi C, Ranieri J, Monti M, Arena U, Iannacone C, Laffi G, Zignego AL. Long-term effect of HCV eradication in patients with mixed cryoglobulinemia: a prospective, controlled, open-label, cohort study. Hepatology 2015; 61:1145-53. [PMID: 25431357 DOI: 10.1002/hep.27623] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Accepted: 11/21/2014] [Indexed: 12/15/2022]
Abstract
UNLABELLED Limited data are available about the efficacy of antiviral treatment in hepatitis C virus (HCV)-associated mixed cryoglobulinemia (MC), especially concerning the long-term effects of HCV eradication. The aim of this study was to evaluate the influence of MC on the virological response and the long-term effects of viral eradication on MC. We prospectively enrolled 424 HCV(+) patients belonging to the following groups: MC syndrome (MCS)-HCV (121 patients with symptomatic MC), MC-HCV (132 patients with asymptomatic MC), and HCV (158 patients without MC). Pegylated interferon plus ribavirin treatment was administered according to standard protocols. Posttreatment follow-up ranged from 35 to 124 months (mean 92.5 months). A significant difference was observed in the rate of sustained virological response between the HCV group and both the MC-HCV (P = 0.009) and MC-HCV+MCS-HCV (P = 0.014) groups. Multivariate logistic regression analysis identified cryoglobulinemia as an independent prognostic factor of nonresponse. The clinical-immunological response in MCS-HCV correlated with the virological one. All patients with sustained virological response also experienced a sustained clinical response, either complete or partial. In the majority of sustained virological response patients all MCS symptoms persistently disappeared (36 patients, 57%); in only two (3%) did definite MCS persist. All virological nonresponders were also clinical nonresponders, in spite of a transient improvement in some cases. No evolution to lymphoma was observed. For the first time we have evaluated both the effects of interferon-based therapy on HCV patients with and without MC and with and without symptoms, as well as the long-term effects of viral eradication on MC. CONCLUSION MC is a negative prognostic factor of virological response. Clearance of HCV led to persistent resolution or improvement of MCS, strongly suggesting the need for a next generation of highly effective antiviral drugs.
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Affiliation(s)
- Laura Gragnani
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Zeremski M, Dimova RB, Benjamin S, Penney MS, Botfield MC, Talal AH. Intrahepatic and Peripheral CXCL10 Expression in Hepatitis C Virus-Infected Patients Treated With Telaprevir, Pegylated Interferon, and Ribavirin. J Infect Dis 2014; 211:1795-9. [PMID: 25512630 DOI: 10.1093/infdis/jiu807] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 12/08/2014] [Indexed: 01/19/2023] Open
Abstract
UNLABELLED We assessed peripheral and liver CXCL10 levels in 15 patients treated with telaprevir/pegylated interferon/ribavirin. Induction of peripheral CXCL10 messenger RNA (mRNA) peaked (mean fold-induction [±SD], 3.1 ± 1.9) between treatment hour 6 and day 2, while induction of intrahepatic CXCL10 mRNA peaked (mean fold-induction [±SD], 1.3 ± 0.54) at hour 10 or day 4. Peripheral CXCL10 levels were higher at treatment hour 10 (P = .032) and day 2 (P = .009) in patients with undetectable virus 2 weeks after treatment initiation. Treatment hour 10 (P = .023) and peak (P = .034) intrahepatic CXCL10 levels were also higher in these patients. CXCL10 did not distinguish treatment responders from nonresponders. In conclusion, CXCL10 identified very rapid virological response in patients treated with a direct-acting antiviral. CLINICAL TRIALS REGISTRATION NCT00892697.
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Affiliation(s)
- Marija Zeremski
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College
| | - Rositsa B Dimova
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine Department of Biostatistics, State University of New York at Buffalo, New York
| | - Samantha Benjamin
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College
| | | | | | - Andrew H Talal
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine
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Hepatitis C virus resistance to interferon therapy: an alarming situation. Open Life Sci 2014. [DOI: 10.2478/s11535-014-0352-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractHepatitis C virus is presently a major public health problem across the globe. The main objective in treating hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). Interferon-α (IFN-α) and pegylated interferon (PegIFN) in combination with Ribavirin (RBV) are the choice of treatment nowadays against chronic hepatitis C. There are several mechanisms evolved by the hepatitis C virus that facilitate the persistence of virus and further lead the patient’s status as non responder. Various factors involved in patient’s lack ofresponse to the therapy include: (1) viral factors, (2) host factors, (3) molecular mechanisms related to the lack of response and (4) social factors. Herein we have made an attempt to summarize all the related predictors of drug resistance in one article so that the future polices can be planned to overcome this obstacle and potential therapies can be designed by considering these factors.
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Wang J, Jiang D, Rao H, Yang R, Wang Y, Wei L. Association of interferon-γ-induced protein-10 serum levels with virological responses to PEG-interferon-based therapy in hepatitis C virus genotype 1 or 2 chronically infected Chinese patients. Scand J Gastroenterol 2014; 49:1349-58. [PMID: 25263691 DOI: 10.3109/00365521.2014.962609] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Interferon (IFN)-γ-induced protein-10 (IP-10) serum level has been shown be associated with viral response in chronic hepatitis C (CHC) patients. However, little is known in Chinese population. We determined IP-10 serum levels in Chinese CHC patients undergoing PEG-IFN-based therapy. Predictive role of IP-10 level for virological responses was accessed. MATERIAL AND METHODS IP-10 serum levels were determined in 165 hepatitis C virus (HCV) genotype 1 and 33 genotype 2 patients. Multivariate analysis was performed to screen independent factors for sustained virological response (SVR) prediction. Predictive value of IP-10 level in combination with interleukin 28B (IL28B) genotype or rapid virological response was further investigated. RESULTS Our study showed that pretreatment IP-10 level was significantly higher in HCV genotype 1 patients. IP-10 levels were independently predictive for SVR with cut-off values of 250.60 pg/ml at baseline or 407.40 pg/ml at week 4. Positive predictive value (PPV) for SVR of low IP-10 level at baseline and IL28B CC genotype was 96.15% and negative predictive value (NPV) was 50.00%. PPV for SVR of low IP-10 level at week 4 and rapid viral response (RVR) was 95.24% and NPV was 50.00%. CONCLUSION Together our study indicated that higher IP-10 serum levels were associated with HCV genotype 1 CHC Chinese patients. IP-10 levels at baseline and week 4 were both predictive of SVR and improved predictive performances of IL28B genotype and RVR for SVR.
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Affiliation(s)
- Jianghua Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases , No.11, Xizhimen South Street, Beijing 100044 , China
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44
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Matsuura K, Watanabe T, Iijima S, Murakami S, Fujiwara K, Orito E, Iio E, Endo M, Kusakabe A, Shinkai N, Miyaki T, Nojiri S, Joh T, Tanaka Y. Serum interferon-gamma-inducible protein-10 concentrations and IL28B genotype associated with responses to pegylated interferon plus ribavirin with and without telaprevir for chronic hepatitis C. Hepatol Res 2014; 44:1208-1216. [PMID: 24372894 DOI: 10.1111/hepr.12294] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 12/12/2013] [Accepted: 12/16/2013] [Indexed: 02/06/2023]
Abstract
AIM Several studies have shown that high pretreatment concentrations of serum interferon-γ-inducible protein-10 (IP-10) are correlated with non-response to pegylated interferon (PEG-IFN) plus ribavirin (RBV) for chronic hepatitis C (CHC). However, there are few reports on their effect on the Asian population. METHODS We enrolled 104 Japanese genotype 1 CHC individuals treated with PEG-IFN/RBV and 45 with PEG-IFN/RBV/telaprevir, and evaluated the impact of pretreatment serum IP-10 concentrations on their virological responses. RESULTS The pretreatment serum IP-10 concentrations were not correlated with IL28B genotype. The receiver-operator curve analysis determined the cut-off value of IP-10 for predicting a sustained virological response (SVR) as 300 pg/mL. In multivariate analysis, the IL28B favorable genotype and IP-10 concentration of less than 300 pg/mL were independent factors for predicting SVR. In a subgroup of patients with the IL28B favorable genotype, the SVR rate was higher in the patients with IP-10 of less than 300 than in those with 300 pg/mL or more, whereas no patient with the IL28B unfavorable genotype and IP-10 of 300 pg/mL or more achieved SVR. Among the patients treated with PEG-IFN/RBV/telaprevir, low pretreatment concentrations of serum IP-10 were associated with a very rapid virological response, defined as undetectable HCV RNA at week 2 after the start of therapy. CONCLUSION Pretreatment serum IP-10 concentrations are associated with treatment efficacy in PEG-IFN/RBV and with early viral kinetics of hepatitis C virus in PEG-IFN/RBV/telaprevir therapy.
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Affiliation(s)
- Kentaro Matsuura
- Department of Virology, Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA
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Zhang S, Zhao Y, Yan H, Wu H, Wei L, Zhang Y, Chen X. Pretreatment serum macrophage inflammatory protein (MIP)-1 levels predict sustained virological responses to re-treatment in patients with chronic hepatitis C virus infection. Int J Infect Dis 2014; 33:15-21. [PMID: 25461236 DOI: 10.1016/j.ijid.2014.08.021] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Revised: 08/26/2014] [Accepted: 08/28/2014] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND There are few predictors of the virological response in patients who are re-treated with antiviral therapies. In this study, we evaluated the levels of chemokines that bind to C-C chemokine receptor type 5 (CCR5) and their impact on combination therapy in both treatment-naïve and treatment-experienced patients chronically infected with hepatitis C virus (HCV). METHODS Longitudinal analysis of CCR5 chemokines was performed using the multiplex Bio-Rad 27-plex assay in 56 treatment-naïve and 24 treatment-experienced patients with chronic HCV infection during combination therapy with peginterferon alfa and ribavirin. A group of healthy donors was included as the control (n=11). RESULTS The pretreatment level of macrophage inflammatory protein 1 (MIP-1) was determined to be an independent predictor, with an ideal predictive threshold for sustained virological response of 95.23 pg/ml. A rapid decline in HCV RNA was observed in patients with a pretreatment MIP-1 level of <95.23 pg/ml, while a slow reduction was measured in patients with levels of ≥95.23 pg/ml (p=0.014). Of note, the dynamics of MIP-1 further indicated that a lower level at baseline and at treatment week 12 was significantly associated with a favorable outcome of antiviral therapy (p=0.014), especially in treatment-experienced patients (p=0.04), while a higher level of MIP-1beta correlated with the elevation of transaminases. CONCLUSIONS Serum MIP-1 is an independent and effective predictor of early and sustained virological response in chronically HCV-infected patients undergoing re-treatment.
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Affiliation(s)
- Shibin Zhang
- Department of Hepatology, Beijing You'an Hospital, Capital Medical University, 100000, Beijing, China
| | - Yan Zhao
- Department of Hepatology, Beijing You'an Hospital, Capital Medical University, 100000, Beijing, China
| | - Huiping Yan
- Department of Hepatology, Beijing You'an Hospital, Capital Medical University, 100000, Beijing, China
| | - Hao Wu
- Department of Hepatology, Beijing You'an Hospital, Capital Medical University, 100000, Beijing, China
| | - Lai Wei
- Hepatology Institute, Peking University, China
| | - Yonghong Zhang
- Department of Hepatology, Beijing You'an Hospital, Capital Medical University, 100000, Beijing, China.
| | - Xinyue Chen
- Department of Hepatology, Beijing You'an Hospital, Capital Medical University, 100000, Beijing, China.
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Bach HH, Wong YM, Tripathi A, Nevins AM, Gamelli RL, Volkman BF, Byron KL, Majetschak M. Chemokine (C-X-C motif) receptor 4 and atypical chemokine receptor 3 regulate vascular α₁-adrenergic receptor function. Mol Med 2014; 20:435-47. [PMID: 25032954 DOI: 10.2119/molmed.2014.00101] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Accepted: 07/14/2014] [Indexed: 12/23/2022] Open
Abstract
Chemokine (C-X-C motif) receptor (CXCR) 4 and atypical chemokine receptor (ACKR) 3 ligands have been reported to modulate cardiovascular function in various disease models. The underlying mechanisms, however, remain unknown. Thus, it was the aim of the present study to determine how pharmacological modulation of CXCR4 and ACKR3 regulate cardiovascular function. In vivo administration of TC14012, a CXCR4 antagonist and ACKR3 agonist, caused cardiovascular collapse in normal animals. During the cardiovascular stress response to hemorrhagic shock, ubiquitin, a CXCR4 agonist, stabilized blood pressure, whereas coactivation of CXCR4 and ACKR3 with CXC chemokine ligand 12 (CXCL12), or blockade of CXCR4 with AMD3100 showed opposite effects. While CXCR4 and ACKR3 ligands did not affect myocardial function, they selectively altered vascular reactivity upon α1-adrenergic receptor (AR) activation in pressure myography experiments. CXCR4 activation with ubiquitin enhanced α1-AR-mediated vasoconstriction, whereas ACKR3 activation with various natural and synthetic ligands antagonized α1-AR-mediated vasoconstriction. The opposing effects of CXCR4 and ACKR3 activation by CXCL12 could be dissected pharmacologically. CXCR4 and ACKR3 ligands did not affect vasoconstriction upon activation of voltage-operated Ca(2+) channels or endothelin receptors. Effects of CXCR4 and ACKR3 agonists on vascular α1-AR responsiveness were independent of the endothelium. These findings suggest that CXCR4 and ACKR3 modulate α1-AR reactivity in vascular smooth muscle and regulate hemodynamics in normal and pathological conditions. Our observations point toward CXCR4 and ACKR3 as new pharmacological targets to control vasoreactivity and blood pressure.
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Affiliation(s)
- Harold H Bach
- Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Yee M Wong
- Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Abhishek Tripathi
- Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Amanda M Nevins
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Richard L Gamelli
- Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Brian F Volkman
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin, United States of America
| | - Kenneth L Byron
- Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois, United States of America
| | - Matthias Majetschak
- Department of Surgery, Loyola University Chicago, Maywood, Illinois, United States of America Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois, United States of America
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Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology 2014; 147:577-594.e1. [PMID: 25066692 DOI: 10.1053/j.gastro.2014.06.043] [Citation(s) in RCA: 587] [Impact Index Per Article: 53.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Revised: 06/05/2014] [Accepted: 06/26/2014] [Indexed: 02/08/2023]
Abstract
Sustained hepatic inflammation is an important factor in progression of chronic liver diseases, including hepatitis C or non-alcoholic steatohepatitis. Liver inflammation is regulated by chemokines, which regulate the migration and activities of hepatocytes, Kupffer cells, hepatic stellate cells, endothelial cells, and circulating immune cells. However, the effects of the different chemokines and their receptors vary during pathogenesis of different liver diseases. During development of chronic viral hepatitis, CCL5 and CXCL10 regulate the cytopathic versus antiviral immune responses of T cells and natural killer cells. During development of nonalcoholic steatohepatitis, CCL2 and its receptor are up-regulated in the liver, where they promote macrophage accumulation, inflammation, fibrosis, and steatosis, as well as in adipose tissue. CCL2 signaling thereby links hepatic and systemic inflammation related to metabolic disorders and insulin resistance. Several chemokine signaling pathways also promote hepatic fibrosis. Recent studies have shown that other chemokines and immune cells have anti-inflammatory and antifibrotic activities. Chemokines and their receptors can also contribute to the pathogenesis of hepatocellular carcinoma, promoting proliferation of cancer cells, the inflammatory microenvironment of the tumor, evasion of the immune response, and angiogenesis. We review the roles of different chemokines in the pathogenesis of liver diseases and their potential use as biomarkers or therapeutic targets.
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Affiliation(s)
- Fabio Marra
- Dipartimento di Medicina Sperimentale e Clinica, University of Florence, Florence, Italy.
| | - Frank Tacke
- Department of Medicine III, RWTH University Hospital Aachen, Aachen, Germany.
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Elezov DS, Kudryavtsev IV, Arsentieva NA, Semenov AV, Esaulenko EV, Basina VV, Totolian AA. ANALYSIS OF T-HELPER SUBSETS OF PERIPHERAL BLOOD OF PATIENTS WITH CHRONIC HEPATITIS C EXPRESSING CHEMOKINE RECEPTORS CXCR3 AND CCR6 AND ACTIVATION MARKERS CD38 AND HLA-DR. ACTA ACUST UNITED AC 2014. [DOI: 10.15789/2220-7619-2013-4-327-334] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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Lin JC, Habersetzer F, Rodriguez-Torres M, Afdhal N, Lawitz EJ, Paulson MS, Zhu Y, Subramanian GM, McHutchison JG, Sulkowski M, Wyles DL, Schooley RT. Interferon γ-induced protein 10 kinetics in treatment-naive versus treatment-experienced patients receiving interferon-free therapy for hepatitis C virus infection: implications for the innate immune response. J Infect Dis 2014; 210:1881-5. [PMID: 24907384 DOI: 10.1093/infdis/jiu325] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
We measured interferon γ-induced protein 10 (IP-10) levels in 428 patients at baseline, week 1, and week 2 of all-oral treatment for hepatitis C virus (HCV) infection. An increased baseline IP-10 level was associated with a T allele in the IL28B gene, an increased alanine aminotransferase level in treatment-naive but not experienced patients, and an increased body mass index. At week 1, the mean decline in plasma IP-10 levels was the same in treatment-naive and treatment-experienced patients (-49%), whereas during week 2 the mean decline in IP-10 levels in treatment-naive patients (-14%) was significantly larger than in treatment-experienced patients (-2%; P = .0176). IP-10 thus may be a surrogate marker of the rate of intracellular viral replication complex decay.
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Affiliation(s)
| | - François Habersetzer
- Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg Inserm 1110 Université de Strasbourg, Strasbourg, France
| | | | - Nezam Afdhal
- Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | | | | | - Yanni Zhu
- Gilead Sciences, Foster City, California
| | | | | | - Mark Sulkowski
- Johns Hopkins University School of Medicine, Baltimore, Maryland
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Lalle E, Bordi L, Caglioti C, Garbuglia AR, Castilletti C, Taibi C, Cristofari F, Capobianchi MR. IFN-Alpha receptor-1 upregulation in PBMC from HCV naïve patients carrying cc genotype. possible role of IFN-lambda. PLoS One 2014; 9:e93434. [PMID: 24691098 PMCID: PMC3972101 DOI: 10.1371/journal.pone.0093434] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Accepted: 03/04/2014] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND AND AIMS IL-28B gene polymorphisms predict better therapeutic response and spontaneous clearance of HCV. Moreover, higher expression of IFN-lambda has been reported in patients with the rs12979860 CC favourable genotype. The study aim was to establish possible relationships between IL-28B rs12979860 genotypes and expression of IFN-alpha receptor-1 (IFNAR-1) in naïve HCV patients, and to explore the possible role of IFN-lambda. METHODS IFNAR-1 mRNA levels were measured in PBMC from naïve patients with chronic hepatitis C with different IL-28 genotypes. The ability of IFN-lambda to up-regulate the expression of IFNAR-1 was established in PBMC from healthy donors carrying different IL-28B genotypes. RESULTS Lower IFNAR-1 mRNA levels were observed in PBMC from HCV-infected naïve patients as compared to healthy donors. In healthy donors, IFNAR-1 mRNA levels were independent from IL-28B genotype, while in HCV patients, an increasing gradient was observed in TT vs CT vs CC carriers. In the latter group, a direct correlation between IFNAR-1 and endogenous IL-28B expression was observed. Moreover, IFN-lambda up-regulated IFNAR-1 expression in normal PBMC in a time-and dose-dependent manner, with a more effective response in CC vs TT carriers. CONCLUSION Endogenous levels of IFN-lambda may be responsible for partial restoration of IFNAR-1 expression in HCV patients with favourable IL-28 genotype. This, in turn, may confer to CC carriers a response advantage to either endogenous or exogenous IFN-alpha, representing the biological basis for the observed association between CC genotype and favourable outcome of either natural infection (clearance vs chronicization) or IFN therapy.
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Affiliation(s)
- Eleonora Lalle
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
| | - Licia Bordi
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
| | - Claudia Caglioti
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
| | - Anna Rosa Garbuglia
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
| | - Concetta Castilletti
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
| | - Chiara Taibi
- Clinical Department, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
| | - Francesca Cristofari
- Clinical Department, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
| | - Maria Rosaria Capobianchi
- Laboratory of Virology, National Institute for Infectious Diseases “Lazzaro Spallanzani,” Rome, Italy
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